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Annu. Rev. Genet. 1975.9:19-38. Downloaded from www.annualreviews.org Access provided by Washburn University on 01/06/15. For personal use only.

XERODERMA PIGMENTOSUM:

+3082

BIOCHEMICAL AND GENETIC CHARACTERISTICS James E. Cleaver Laboratory of Radiobiology, University of California, San Francisco, California 94 143

D. Bootsma Departm ent of Cell Biology and Genetics, Erasmus University, Rotterdam, the Netherlands

INTRODUCTION: CLINICAL FEATURES OF XERODERMA PIGMENTOSUM Xeroderma pigmentosum (XP) is an autosomal recessive human skin disease whose outstanding clinical characteristic is a marked predisposition to develop skin cancers after exposure to sunlight. This disease representll a unique conjunc­ tion of both genetic and environmental factors in cancer etiology, and for this reason elucidation of its biochemical basis may provide clues to understanding the genetic changes involved in carcinogenesis from many chemical and physical agents. The disease was first described by Hebra & Kaposi in

1 874 (I), and at that

time the roles of both inheritance and sunlight were clearly recognized.. Much later, detailed clinical studies of a wide range of patients showed that the nature and severity of cutaneous, ocular, and neurological symptoms vary widely with genetic makeup and amount of sun exposure (for review, see reference

2). The

typical progression of the disease consists of an early stage in the first years of life in which the erythemal response to sunlight may be abnormal. The abnormality involves a prolonged latent period, atypical morphology, and a lower than normal minimal erythemal dose

(3). The erythemal response can

be used in early diagnosis before skin changes develop. After several years of life, other skin changes, including excessive freckling, keratoses, and cancers, develop. The pigmentary changes and frequent recurrences of cancers in sun­ exposed regions of the skin are the characteristic features on which diagnosis

19

20

CLEA VER & BOOTSMA

is based. These cancers involve all cell types that receive sun exposure and include squamous and basal cell carcinomas, malignant melanomas, keratoa­ canthomas, angiomas, and sarcomas A few patients diagnosed from these late symptoms as having XP exhibit a completely normal erythemal response, which may be a distinctive feature of the form known as the XP variant (3-6). Neurological disorders associated with XP were first recognized by deSanctis & Cacchione in 1932 (7). These symptoms include microcephaly, progressive mental deficiency, retarded growth and sexual development, deafness, ataxia and choreoathetosis, and areflexia. Many XP patients with neurological involve­ ment do not exhibit this full range of disorders, known as the deSanctis­ Cacchione syndrome, but show only one or a few of them. Pathological studies of XP patients with central nervous system (eNS) involvement show neuronal deficiency or loss without distinctive features (2, 8). There is as yet no cure for XP. Treatment consists of minimizing exposure to sunlight and regular dermatological care with surgery when necessary for recurrent tumors. Success in prenatal diagnosis has recently been achieved by Ramsey et al (9), and this can now be routinely performed when there is a known risk of an XP child because of previous cases in the family.

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.

CELLULAR PHENOTYPE OF XERODERMA PIGMENTOSUM Karyotype The karyotype of most XP patients is apparently normal, with no d'istinctive chromosomal abnormalities such as seen in some conditions like Down's syn­ drome, Klinefelter's syndrome, Bloom's syndrome, etc (10). Sister chromatid exchanges are also within the normal range (II). Isolated reports have been made of karyotypic abnormalities-reciprocal exchanges were described in a small percentage of cells from one XP patient (12), and one of a pair of sisters with the deSanctis-Cacchione syndrome was reported to have an extra chromo­ some (13), but these abnormalities seem to have no general significance for the disease. Chromosome aberrations can be induced in human cells by radiations and carcinogenic chemicals. Irradiation of normal and XP cells by UV light induces chromatid and chromosome aberrations, and one study indicates that more chromatid aberrations are found in XP cells than in normal cells 24 hr after irradiation (14). Since this study was done at only one time after irradiation, it is insufficient to show that XP cells are more prone than normal cells to UV-induced aberration production. Sasaki (15) showed that XP lymphocytes were more prone than normal cells to growth delay and chromosome aberration production by 4-nitroquinoline-I-oxide but were the same as normal cells in response to methylmethane sulfonate. Since repair of 4-nitroquinoline- l -oxide damage (16, 17) but not of methylmethane sulfonate damage (I8) is defective in XP cells, high levels of chromosome aberrations must be associated with defective repair of DNA.

XERODERMA PIGMENTOSUM

21

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Cell Killing and Host Cell Reactivation after Irradiation or Exposure to Chemical Carcinogens

Two phenotypic characteristics of XP cells in culture! that correspond to the clinical symptoms of high UV sensitivity are their colony-forming ability after irradiation and their reduced ability to support growth of UV-damaged viruses. The first demonstration of the high sensitivity of XP cells to UV light was based on a determination of total protein per culture 10 days after irradiation (19). But this important clue to the cellular basis of XP was generally ignored. Several years later it was found that the colony-forming ability of most forms of XP is much more affected than normal cells by UV light; the sensitivity increase corresponds to a dose-modifying factor of 3 to 10 (20-23) (Figure I). XP cells were also found to be more sensitive to 4-nitroquinoline- l -oxide and benz(a)anthracene and a variety of aromatic amides but normal in response to N-methyl-N'-nitro-N-nitrosoguanidine (22-25). Since these studies were all done with fibroblasts that had low pl a t ing efficiencies (1-10%), the precise values of extrapolation number and D02 cannot be regarded as accurate parame-

\ \

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XP6

\

\ \ \

0.01

-

20

40 UV DOSE

60

80

100

120

iergs/mm2\

Figure 1 Survival curve for normal and XP fibroblasts irradiated with UV light. Normal fibroblasts (.,. ) ; xeroderma pigmentosum fibroblasts-XP6SF (e); tw o unrelated xero­ derma pigmentosum variants-XPl4SF (0) and XPI 6SF (0). [Reproduced from Cleaver (5) with perm iss io n from Williams & Wilkins.]

! Representative cultures are available from cell banks in both the American Type Culture

Collection, 12301 Parklawn Drive, Rockville, Maryland 20852 and the Mammalian Genetic Muta nt Cell Repository, Institute for Medical Research, Copewood Street. Camden, New Jersey 08103. In comparative studies the nomenclature adopted to identify XP cell lines is in the form: "XP-number-Ietter designation of laboratory or city of origin" (51). Thus, ce ll lines from Rotterdam are XPIRO, XP2RO, etc, those from San Francisco are XPISF, XP2SF, etc, and other letters are chosen as appropriate. Heterozygotes are correspondingly identified as XPHISF, XPH2SF, etc. 2Do is the dose required to reduce survival by lie on the exponential portion of the survival curve.

Annu. Rev. Genet. 1975.9:19-38. Downloaded from www.annualreviews.org Access provided by Washburn University on 01/06/15. For personal use only.

22

CLEA VER & BOOTSMA

ters of the XP cells and cannot be correlated closely with the clinical symptoms of the XP patients. The XP variant is an exception-its cell survival curve is either indistinguishable from normal (5) (Figure I) or shows a slight increase in sensitivity after UV irradiation (V. M. Maher, Michigan Cancer Foundation, Detroit, personal communication, 1975). The survival of various UV-i r r adiate d viruses grown in XP cells is less th an in normal cells (Figure 2). This indicates that the host cell genetic defects are important in viral reproduction, a phenomenon known as host cell reactivation. Lower survival has been reported for Herpes simplex (26, 27), Simian Virus 40 (SV 40) (28), adenovirus ( 29, 30), and vaccinia (27, 31), all of which are DNA viruses. In addition there is one report that the free RNA, but not the intact virus, from encephalomyocarditis virus shows host cell reactivation (31). The XP variant shows a slight reduction in survival of UV-damaged adenovirus (29, 30) but is indistinguishable from normal cells for growth of UV -damaged Herpes virus (c. D. Lytle, Twinbrook Research Laboratory, Rockville, Maryland, personal communication, 1974). The 03/ of irradiat ed viruses grown in XP cel ls is about 20 times less than in normal cell strains for adenovirus (29) and about 3 times l e ss for H erp es virus (26, 27), which impl i es that adenovirus may be more dependent than Herpes virus on host cell enzymes. The D37 for adenovirus in XP cells corresponds to the production of about one pyrimidine dimer per viral genome. The reduction

Figure 2

Ultraviolet inactivation kinetics of adenovirus 2 grown in normal and XP variant

cell lines. Left,

(0, e)

normal fibroblasts:

(.,6, . 0) ,

XP homozygote cell lines.

[Reproduced from Day (30) with permisSion from Pergamon Press.] Center and righI,

. . ) normal cell lines: (e,., 6,0, 0 ) XP va riant Day (32) with permission frum Macmillan Journals Ltd.] '

(0,

cell lines. [Reproduced from

:In" is the dose required to reduce survival to 37% of cont ro l .

XERODERMA PIGMENTOSUM

in 037 for adenovirus in several XP variant strains is less than two

23

(32). These

observations imply that the genetic defects in XP variant cell lines are much less important for the survival of radiation-damaged cells and viruses than are the defects in the other forms of XP. But since all forms of X P show similar skin symptoms, the genetic defects appear to be equally important for car­ cinogenesis.

SV40 Transformation of Xeroderma Pigmentosum Cells In a few high cancer diseases, cultured fihrohlasts are reported to be transformed

Annu. Rev. Genet. 1975.9:19-38. Downloaded from www.annualreviews.org Access provided by Washburn University on 01/06/15. For personal use only.

by SV40 at abnormally high levels

(33). However, studies with XP cells have

given widely varied results, with transformation frequencies higher, lower, and similar to those of normal cells

(14, 28, 34, 35). Irradiation of cells before

infection with SV 40 decreases the transformation frequency identically in normal and XP cells

(36). Transformed XP cells carrying integrated SV40 genomes

are unchanged in their DNA repair capacity (14, 20, 36). XP therefore does not seem to exhibit any special properties in response to SV 40 infection.

BIOCHEMICAL CHARACTERISTICS OF XERODERMA PIGMENTOSUM Biochemical Defects in the Common and deSanctis-Cacchione Forms of Xeroderma Pigmentosum The first clue to the hiochemistry of XP came from studies of repair of UV damage in cultured fibroblasts from patients with both the common and the deSanctis-Cacchione forms of XP

(37, 38). These studies showed that XP cells

are defective to various degrees in their ability to perform excision repair of

3) and that the common and neurological forms of

damaged DNA (Figure

XP are qualitatively similar. The first demonstration of a defect showed that a late step of excision repair involving the insertion of new bases-repair replica­ tion (or unscheduled synthesis)-is reduced in several cases of XP

(37). This

finding has been confirmed and extended by subsequent studies (36, 38-40).

XP cells were later shown to be defective in an earlier stage of excision repair: their ability to excise UV -induced cyclobutane pyrimidine dimers is less than in normal cells (3 9, 40). Cells from various XP patients show the excision defect to varying degrees: some are unable to excise dimers to any measurable extent: others are able to excise at lower levels than normal cells (41) (Figure

4).

As a consequence

of the reduced ability of X P cells to excise dimers, the insertion of new bases

(for revil:w

51:1:

rderence 42) after excision is also reduced

(37) (Figure 5). XP

cells from different patients exhibit levels o f repair replication between 0 and about 90% of normal

(Figure 5),

with affected

sibs usua lly

similar to one

another. Heterozygotes are in general indistinguishable from normal cells in dimer excision and repair replication

(20, 36, 42).

The variation in amount of dimer excision and repair replication is an indica­ tion of possible biochemical and genetic differences between different XP

24

('LEA VER & BOOTSMA

I � bose

damage ...'

Annu. Rev. Genet. 1975.9:19-38. Downloaded from www.annualreviews.org Access provided by Washburn University on 01/06/15. For personal use only.

,.' I I

", , \ I I

!I t

!

I

J '::0 t:

EXCISION REPAIR (1 to 100 bases/patch in parental strands)

POST REPLICATION REPAIR {up to 1000 boses/ gop in daughter strands}

DNA I I REPlICATtON I

:I � \

,

C"'

'�/...

Figure 3

Schematic representation of excision repair and postreplication repair mecha­

nisms operating in the vicinity of semiconservative DNA replication occurring bidirec­ tionally with DNA damage behind and in front of replicating forks. Excision repair involves sequential incision, excision, repair replication, and sealing of a small patch that replaces the initial damage. Postreplication repair involves gaps left in newly synthesized strands opposite damage on parental strands, which are slowly filled in by de novo synthesis that extends the new strands from the vicinity of the dimer toward the replicating forks.

patients. Since there is a superficial similarity between XP and Escherichia coli Uvr- strains we might expect XP to include human analogs of the uvrA, -B, -C, and -D loci. E. coli uvrA and -B lack the initiating UV repair endonuclease, and E. coli uvrC has a later defect in excision (43). The difference between these bacterial strains can be detected by measuring the production of single­ strand breaks during repair of UV damage using alkaline sucrose gradient tech­ niques (44). Attempts to determine whether XP cells have a UV endonuclease that would make single-strand breaks in DNA after irradiation are, however, inconclusive. When human fibroblasts are lysed to observe molecular weight changes associated with single-strand breaks, the'rargest control single-strand DNA molecules obtainable are approximately (2-5) X 108 daltons (45, 46). Breaks associated with excision repair of UV damage are generally less frequent than I per 2 X 108 daltons (46, 47), and excision-related breaks have been difficult or impossible to detect in normal cells (39, 45, 47). These results, and those obtained from kinetics of dimer excision (40) and repair replication (48), imply that the capacity of excision repair is limited and that the UV endonuclease that initiates excision is in low concentration [< 104/cell (47)]. The opposite

XERODERMA PIGMENTOSUM

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Annu. Rev. Genet. 1975.9:19-38. Downloaded from www.annualreviews.org Access provided by Washburn University on 01/06/15. For personal use only.

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25

0

0

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20

20 20

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INCUBATION

Figure

4

Left,

TIME

Ih I

30

10

o

20 INCUBATION TIME

Ih I

30

time course of disappearance of UV endonuclease-susceptible sites from

the DNA of normal human cells irradiated with 254-nm radiation. After specified periods of post-UV incubation, cell samples were assayed to determine the number of nuclease-sus­ ceptible sites remaining in the extracted DNA. The percentages shown for the incubated samples are relative to those found for the parallel nonincubated ones. Each point is the arithmetic mean of two or more independent determinations. Incident UV dose (erg/mm" ) :

(e)

65, (0) 125, (0) 250, (.) 500. RighI, the relative time course of disappearance of

UV endonuclease-susceptible sites

from the DNA of several XP strains exposed to 250 erg/mm" of 254-nm radiation. For comparison, corresponding data for normal cells are replotted here. Each point is the

arithmetic mean of two independent determinations. (0) XP4, (6) XP5, (e) XPI2, (.) XP25, (A) XP26, (0) normal cells. [Reproduced from Paterson et al (41) with permission from Elsevier Scientific Publishing Company.]

conclusion, implying enzyme excess, however, can be derived from cell hybrid­ ization studies (49). Some alkaline sucrose techniques produce fast-sedimenting DNA species, and these are sufficiently large that changes in sedimentation properties can be detected during excision repair (46, 50). Studies using these techniques indicate that XP cells from both n e uro logical and nonn eL r oiogicai forms of XP lack the abili t y, seen in normal cells, of making breaks soon after irradiation (46, 51). Discrimination between the different forms of XP has not, h ow e v er p r ov ed practicable by this te chniq ue , and morc detailed biochemical characterization 1

,

must depend on isolation of repair enzymes.

UV -repair enzymes in human cells have not thus fa r c l ea rl y UV endonucleases specific for pyrimidine dimer excision. Both Bac­

Initial studies of identified

chetti et al (52) and Brent (53) have obtained cell extracts of normal and XP

cells that contain enzyme(s) that w ill m ake e ndonucle oly tic breaks in UV -ir­ radiated DNA. But this endonucleolytic act ivity is not specific for dimers. because

26

CLEAVER & BOOTSMA 80 e •

_-:::__�c:r-----' - -

e . •

Annu. Rev. Genet. 1975.9:19-38. Downloaded from www.annualreviews.org Access provided by Washburn University on 01/06/15. For personal use only.

....0--

-

_-

200

Erg/mm2

Figure 5

300

400

500

UV LIGHT

Average grain number over nuclei of cells labeled by unscheduled synthesis.

Cultures labeled with 3H-thymidine ( 1 0 p.Ci/ml. 20 Cilmmol) for 3 hr after irradiation

(e) XP heterozygous fibroblasts. (0.0) XP homozygous fibroblasts (affected siblings. XP20SF. XP2ISF). (,6) XP homozygous fibroblasts (XP23SF).

with UV light. (.) normal human fibroblasts.

specific removal of dimers by photoreactivation leaves other UV -induced lesions that are substrates for the enzyme activity. A human UV endonuclease that is dimcr-specific has been described ( 54), but this is labile and easily destroyed by freezing. Most XP cells do. however, appear to possess exonucleolytic activity for dimers: extracts of XP cells that have been frozen and thawed and supple­ mented with a UV endonuclease from T4 phage can excise pyrimidine dimers in vitro (K. Cook, E. C. Friedberg, & J. E. Cleaver, manuscript submitted to Nature for publication). Cell Hybridization and Complementation Groups

Genetic heterogeneity in XP patients whose cells are defective in excision repair (i.e. the common and neurological forms but not the variant) is suggested by the different residual activities of repair replication observed in cells from different patients (2, 20, 36, 37, 45, 48). Cells from afflicted members of one family perform the same amount of repair replication, indicating that the level of repair is inherited as a distinct gen etic trait. Hybridization of cells from different patients in vitro has provided a new approach to the study of genetic heterogeneity and has made possible complementation tests comparable to those available for microorganisms. De Weerd-Kastelein et al (55) demonstrated normal levels of unscheduled synthesis in hybrid binuclear cells obtained after fusion of cells from a nonneurological XP patient and a deSanctis-Cacchione patient. This observation implied that these two patients belonged to different complementation groups. In later studies these investigators found a third com­ plementation group composed of two related patients whose cells perform 40 to 50% of the normal level of unscheduled synthesis (56). Subsequent work

27

XERODERMA PIGMENTOSUM

detected four different complementation groups in XP (2). A comparison of these four complementation groups with the three described by de Weerd-Kas­ telein et al (55, 56) resulted in the identification of five complementation groups within the excision-repair-defective XP syndrome (57, 58) (Table I).

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Table 1

Complementation groups in xeroderma pigmentosum

Complementa tion groupa

Cell stra insb

Neurologica l a bnorma litiesC

References

A

XP12RO XP25RO XP26RO XP 1 LO XP4LO XPK MSF XPPKSF XPl7SF XPl2BE

+ + +

55 59 56 2, 57 56 2, 57 56 56 2, 57

B

XP liBE

+

C

XP4RO XP9RO XP l6RO XP20RO XP2 l RO XPl2SF XPIBE XP2BE XP3BE XP8BE XPIOBE XPl4BE

a

o

XPSBE XP6BE XP7BE

E

XP2RO XP3RO

+ + + + +

56

56 2, 57 2, 57 2, 57 2, 57 2 , 57 2, 57

(2).

b All strains from individuals clinically diagnosed as

2, 57 2, 57 2, 57

+ + +

56

56

The complementation groups are identified according to

et al

2, 57 55 55 55 56

XP

the

nomenclature proposed by Robbins

patients are called

XP.

The strains are

further characterized by a serial number or by two letters (the patient's initials) given in the institute where the cells were brought into culture and by two letters denoting the institute or the city where

(51). XP patients

it is located C

Many

exhibit only one or a rew neurological abnormalities. The full range of these

abnormalities, known as the deSanctis-Cacchione syndrome, appears in very rew

presence of neurological symptoms is denoted by + and the absence by -.

XP

patients. The

28

CLEAVER & BOOTSMA

Biochemical analyses of cell populations formed by fusion between different

XP cells lines can be performed on cultures in which a very high perccntage

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of the nuclei is present in multinuclear cells (59). Normal kinetics for both

repair replication and disappearance of dimer-containing sites are exhibited by these heterokaryons after complementation (41). Patients showing neurological involvement can be classified in three different complementation groups (Table 2): groups A, B, and D, but pati en ts with markedly different degrees of neurological manifestations (c.g. XPKMSF and XPI2BE) fit into the same complementation group (2, 57) (group A, Table I). One patient, apparently without neurological symptoms (XPILO), is also listed in group A, but this patient provides the only exception so far, and in general XP patients with neurological disorders form distinct complementation groups from the patients with the common form of XP. A good correlation exists between the residual level of repair and the c omplem entation groups (Table 2). Very low or negligible levels of repair are found in cell strains belonging to complementation group A. It is higher in groups B and C (5-20%) and highest (25-50%) in groups D and E. Recent studies by Sutherland et al (60) indicate that low levels of photoreactivating enzyme are associated with low excision repair in each of the complementation groups. The existence of five distinct complementation groups in XP patients whose cells exhibit defective DNA repair indicates intergenic rather than intragenic complementation. The affected genes may play a role as structural or regulatory genes in the formation of one or more enzymes mediating the first steps of the excision repair process in human cells. It might he postulated that the excision repair enzymes act in a coordinated way by means of an enzyme complex (45 , 47,61). The association of reduced photoreactivation with reduced excision repair in XP also suggests some form of coordinated control of repair systems (60).

One implication of these hypotheses is that mutations affecting one of the enzymatic steps could prevent the complex from progressing along the DNA

Table 2

Levels of unscheduled synthesis in the complementation groups of XP

Complementation groups Neurological form

A B

Neurological form

C

Common form

D

E

Percentage of repair in normal cellsa

References

2

58

5

45

3-7

58

10-20

58

5-15

45

Neurological form

25-50

58

Common form

40-50

45,59

a

Unscheduled synthesis was measured by labeling with "H-thymidine for 3 hr or less immediately " after a dose of either 100 erg/mm' (45) or 150 erg/mm (58) and then counting grain numbers in autoradiographs.

XERODERMA PIGMENTOSUM

29

from one lesion to the next. This hypothesis would then predict that all mutations, even those affecting late steps of the excision repair process, could appear as defects in an initial step of the repair mechanism. The existence of an enzyme complex for repair seems unlikely, however, because complete DNA repair can be performed in vitro by separated purified repair enzymes (43) and supple­ mentation of homogenates from XP cells of several complementation groups

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with purified T4 UV-endonuclease enables in vitro pyrimidine dimer excision to occur (K. Cook, E. C. Friedberg & J. E. Cleaver, manuscript submitted for publication). The existence of numerous complementation groups therefore probably implies multiple gene loci specifying subunits and cofactors of the UV endonuclease that initiates repair in XP cells. Biochemical Defects in the Xeroderma Pigmentosum Variant and the Role of Caffeine in DNA Repair The XP variant was identified as any patient who was clinically diagnosed as having XP but whose cells showed normal excision repair (4-6) and did not seem abnormally sensitive to UV light (5). The apparently normal UV sensitivity was taken to imply that the XP variant did not lack any DNA repair processes. However, later work (62) has shown that XP variant cells are actually defective in a stage of postreplication repair (Figure 3) and are slightly reduced in host cell reactivation of UV -damaged adenovirus (3�, 32). In retrospect, early data (5) should therefore be interpreted to mean that postreplieation repair is less important than excision repair for survival of human cells, though of obvious importance to the clinical symptoms of the XP variant. Postreplication repair is most evident as an acute response in cells that attempt to replicate DNA semiconservatively soon after experiencing damage from radiation or chemical carcinogens (Figure 3). Damaged bases on parental strands cause interruptions to be left in newly synthesized daughter strands, and these show up as a reduction in single-strand molecular weights observed in alkaline sucrose gradients (63 70). The gaps are subsequently filled. thus increasing the single-strand molecular weight of DNA made soon after irradiation. and the molecular weights observed experimentally are functions of the durations of labeling with radioactive thymidine and the rates of DNA chain elongation. gap formation, and gap sealing. When postreplieation repair is observed by pulse labeling with :lH-thymidine many hours after irradiation, the DNA single-strand molecular weights are within the normal range and gap formation is not detected, even in rodent and XP cells that fail to excise pyrimidine dimers (64, 71, 72). This recovery of the ability to synthesize high molecular weight DNA has not been satisfactorily explained. It may be due to an increase in the rate of gap filling at late times. the involvement of lesions other than pyrimidine dimers [although photoreac­ tivation experiments with marsupial cells (73) do implicate dimers in postrepli­ cation repair], some conformation change in DNA lesions to minimize gap formation, or a rearrangement in the pattern of initiation and termination sites of replicon synthesis.

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30

CLEAVER & BOOTSMA

XP cell lines from excision-repair-deficient complementation groups show a slower pattern of gap formation, gap filling, and recovery of their ability to synthesize high molecular weight DNA than do normal fibroblasts (62, 65, 66). Cells from several XP variant patients, however, have a rate of gap filling that is very much slower than normal fibroblasts (62). This form of XP therefore must have some defect in postreplication repair. Postreplication repair can be inhibited by caffeine and theophylline (62, 74, 75). These drugs occupy a unique position in UV photobiology, because they are the only compounds known that specifically inhibit a DNA repair process in mammalian cells (63, 68, 75, 76). All other drugs that inhibit excision repair or postreplication repair do so nonspecifically and also affect normal semicon­ servative DNA replication or have other toxic cellular effects (77). The effect of caffeine on postreplication repair and cell survival depends on the relative importance of postreplication repair in a given cell type. In normal human cells, in which excision repair is the dominant UV repair system, only minor effects of caffeine on gap filling or cell survival are detected (74, 78). In ex­ cision-repair-defective XP cells, in which cell survival depends on postreplication repair, greater effects of caffeine on gap filling are observed (62, 74). In the XP variant, however, gap filling is drastically inhibited by caffeine (62). The biochemical mechanism by which caffeine exerts these effects on post­ replication repair has not yet been explained. Two possible explanations are that caffeine inhibits phosphodiesterases and thereby causes an increase in intracellular cAMP levels or that caffeine binds to the single-stranded regions of DNA present during gap formation in postreplication repair and prevents their sealing. Both of these interpretations presuppose that caffeine acts as caffeine within the cell. In fact, caffeine is metabolized rapidly in human and rodent cells by demethylation and is converted into adenine and guanine (79). Thus, an effect on DNA replication and postreplication repair mediated through a general increase in purine pool sizes and consequent enzyme inhibition can also be envisaged.

DNA Repair in Xeroderma Pigmentosum Heterozygotes Heterozygous cell lines show DNA repair levels that are within the range of normal cell lines (20, 36, 48). Only occasionally have reports been made of heterozygotes with reduced repair levels (5, 80), and these remain unconfirmed. Since repair levels cannot therefore be used to identify heterozygotes, several other methods have been attempted. In one method, ethylmethane sulfonate was used as a mutagen to produce repair-deficient cells from normal or presumed heterozygous cell lines (51). Since normal cells are homozygous wild type ( + / + ) for repair, in contrast to heterozygotes (+ /XP), the mutation frequency to homozygous repair-deficient (XP /XP) was higher for heterozygotes (0.34-0.39%) than for wild type (0.035-0.11%). This method, although giving results that discriminate heterozygotes from wild-type cells, proves difficult to use routinely because autoradiographs have to be scored to detect less than 1% repair-deficient cells in a population treated with the mutagen. A more practicable method consists of making multinucleate hybrid cells

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XERODERMA PIGMENTOSUM

31

between presumptive heterozygote cells and homozygous XP cells (49). When several nuclei coexist in the same cytoplasm, a stage can be reached at which the gene products from the one wild-type genome in the XP heterozygous nucleus cannot repair UV damage throughout all nuclei at normal rates. A single XP heterozygous nucleus in a heterokaryon can maintain DNA repair at normal levels in fewer XP nuclei than can a normal nucleus. Reduced levels of unsched­ uled synthesis in such multinucleate hybrid cells indicate that although het­ erozygous cells appear to have excess repair capacity, there is a limit. Unrelated heterozygotes seem to show subtle differences is reduced in multinucleate heterokaryons as a function of the number of XP nuclei. These differences have been interpreted in terms of association between the enzymes or polypeptides of the repair system to form an enzyme complex (49). Although this idea has been frequently advocated (45. 47, 49, 61). no direct evidence supports it.

Response of Xeroderma Pigmentosum Cells to Various Mutagens and Chemical Carcinogens The response of XP cells to various chemical carcinogens and mutagens depends on the nature of the reaction between the chemicals and DNA. These chemicals interact as electrophilic reagents with nucleic acids, proteins. and other macro­ molecules in cells. Some carcinogens and mutagens are electrophilic reagents themselves (e.g. alkylating agents: methylmethane sulfonate. propane sultone. methyl nitrosourea) whereas others require metabolic conversion by cellular enzymes into electrophilic reagents [e.g. 4-nitroquinoline-I-oxide, acetylamino­ fluorene, benz(a)anthracenej. The products of the reactions between carcinogen and DNA, which constitute damage to DNA, are mended by excision repair in normal cells. The amount of repair and the extent of cell killing in XP cells, however, appear to depend on whether the damage to DNA involves strand breaks. One can envisage that damage that does not involve a strand break will require endonucleolytic action to initiate excision repair whereas strand breaks will not require an endonuclease. This kind of argument was used to infer that the reason XP cells can repair X-ray damage but not UV damage is that they lack the initiating UV endonuclease (38, 81). A majority of chemical carcinogens appear to modify DNA bases without causing strand breaks, and XP cells exposed to such chemicals perform lower amounts of repair replication than do normal cells (25, 82-84) and are more sensitive to cell killing (22, 23. 25). Agents that, like X-rays, cause DNA strand breaks result in normal levels of repair in XP cells (18, 38, 81, 84). Chemical mutagens and carcinogens can be divided into two broad categories on this basis (Table 3). The precise biological significance of this classification is unclear ' at present because chemicals in both categories are carcinogens. Alkylating agents and X rays seem to be the more potent (85). and far fewer lesions per genome are required for cell killing and mutagenesis by X rays than by UV light (86. 87). In normal cells the damage that can be repaired in XP cells appears to involve smaller patch sizes than the other agents (88, 89). The use of this classification as a basis for screening for potential carcinogens

CLEA VER & BOOTSMA

32 Table 3 cells"-

Classification of carcinogens and mutagens on the basis of DNA repair in XP

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Agents causing damage repaired d efec tiv ely in XP cells UV light Methoxypsoralen adduct 4-N itroq uinoline- l -oxide Bromobenz(a )anthracene Benz(a)anthracene epoxide 1- N itropyridine-I-oxide Acetylaminoftuorene a References:

Agents causing damage repaired defectively in XP cells X rays Bromouracil photoproducts Methylmethane sulfonate N-methyl-N'-nitro-N-nitrosoguanidine Methyl nitrosourea ICR 170

18,22-24,37,80,82, 83, 88, 109.

by finding agents to which XP cells exhibit decreased repair, or increased sensitivity (90), seems limited, because such a search would fail to identify X rays and alkylating agents as carcinogens. The relative sensitivity of XP cells and the number of new bases incorporated into their DNA by excision repair depend on the detailed chemistry of the DNA damage and its repair but do not appear to be correlated in any simple manner with the mutagenic and carcinogenic potential of a chemical. OTHER HIGH AND LOW REPAIR DISEASES

Ever since the discovery of an association between defective excIsIon repair and XP there has been a concerted effort to find other diseases in which repair is altered. None have yet been found that are as clear as XP. Progeria, a premature aging disease, has attracted considerable attention because cells from progeria patients and other patients whose cells are sensitive to X rays are defective in rejoining X-ray-induced single-strand breaks in DNA (91). But progeria's DNA-rejoining kinetics are influenced markedly by culture conditions, so the repair phenomenon may not be the primary genetic defect but a consequence of some other metabolic defect that l:auses the aging symptoms (92, 93). Various other isolated reports have been made of associations between repair and disease, but in most cases these have remained unconfirmed and are proba­ bly to be discounted. Bloom's disease, in which there are high levels of sponta­ neous aberrations (12, 94), has normal excision r epa ir (48). In Fanconi's anemia a small reduction in excision repair at high UV doses was interpreted as due to defective UV exonucleolytic activity (95). Chronic lymphocytic leukemic cells (96) and fibroblasts from patients with chronic actinic keratosis (1. Pitts, Glasgow University, personal communication, 1974) have been reported to exhibit high levels of excision repair. A disease similar to actinic keratosis, which has been designated "pigmented xerodermoid"

XERODERMA PIGMENTOSUM

33

(97), is supposed to be abnormally sensitive to inhibition of DNA synthesis by UV light, but this has not been confirmed in fibroblast cultures, and the disease itself does not seem clearly defined. An animal with a repair-deficient disease would greatly facilitate work to elucidate the relationships between clinical symptoms and biochemical defects, but despite some searching none has yet been reported (47, 80).

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POSSIBLE SIGNIFICANCE OF DNA REPAIR IN THEORIES OF AGING AND CARCINOGENESIS There are theories of aging (98, 99) and carcinogenesis (100) that invoke an accumulation of genetic damage as part of the underlying mechanisms. On the one hand, the accumulation of damage would progressively decrease the fitness of somatic cells with age (99); on the other, damage in critical regions of the genome would result in somatic mutations that make somatic cells malig­ nant (98). In these theories DNA repair has a self-evident role: inefficient or inaccurate repair should be correlated in various ways with increased rates of aging and carcinogenesis. Experimental evidence involving clinical and biochem­ ical features of XP and other human diseases bears on the strength and validity of these theories. Aging theories involving repair processes find little support from studies of XP. XP patients and XP cells in vitro show none of the signs of premature aging that should be observed if defective excision repair of base damage has any bearing on the aging process (2, 21). The progressive loss of neurons in the neurological forms of XP could be ag e related, however, because base damage from physical and chemical agents in nondividing brain cells could cause an abnormal rate of cell death. In progeria, some alteration in repair of single-strand breaks in DNA is observed (91-93). But the experimental evidence surrounding this disease is conflicting, and the repair defects might be a consequence rather than a cause of the disease. In normal primary human tissue cultures several distinct phases of aging in vitro are discernible (101), but no progressive changes in excision repair can be detected before the latest phases of senescence set in (21, 102). Only in one instance is there evidence supporting a correlation between aging and excision repair: Hart & Setlow (103) found an apparent correlation between life span and the relative amount of excision repair of UV damage performed by cell cultures of various mammalian species. This correlation, however, was based on a small number of species and did not take into account the wide variation in possible life spans within murine species, the decrease in excision repair that occurs over the few transfers of mouse cells in culture (104), and the five- to tenfold variation in excision repair observed in hamster cells (80). Aging, therefore, does not seem to find a ready explanation in terms of DNA repair processes, at least on the basis of current evidence. DNA repair does find a logical place in theories of carcinogenesis induced by physical and chemical carcinogens. Since a close correlation exists between

o

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34

CLEAVER & BOOTSMA

the mutagenic and carcinogenic activity of many chemical agents (105), It IS easy to envisage that DNA damage that is repaired defectively can result in mutagenesis and that mutation of some critical region of the genome is an important step in carcinogenesis. The association of defective excision repair of UV damage with UV-induced skin cancer in XP, the defective repair of 06 alkylated guanine in the brain where ethyl nitrosourea induces tumors (106), and the photoreactivation of UV-induced thyroid tumors in fish (107) all point to a connection between the amount of DNA damage and the efficiency of its repair as being an important factor in induced carcinogenesis. Important evidence in support of this connection is the demonstration that XP cells in culture show an expected increase in UV-induced mutation frequencies in comparison to normal cells (108). Since similar clinical symptoms are exhibited by both excision-repair-defective and postreplication-repair-defective XP pa­ tients, we may infer that although the former repair system is paramount for cell survival (5, 20), both systems are important in preventing radiation-induced genetic changes. Further studies of the various repair systems, the clinical forms of XP, and particularly the mutagenic effects of UV light in XP are obviously in order. XP is still a fertile field of study as a model system for radiation­ and chemically induced carcinogenesis. ACKNOWLEDGMENT

J.E.C. is supported by the US Energy Research and Development Administra­ tion. Literature Cited 1. Hebra, F., Kaposi, M. 1874 . On Dis­ eases of the Skin, Includin the .Ex­ anthemata, 3:252-58. Trans . W. Tay. London: New Sydenham. Soc. 2. Robbins. J. H .. Kraemer, K. H., Lutzner, M . A., Festoff, H. G. 1974. Xeroderma pigmentosum: An inherited disease With sun sensi­ tivity, multiple cutaneous neoplasms, and abnormal DNA repair. A nn. In­ tern. Med. 80:221-48 3. Ramsey, C A., Giannelli, F. 1975. The erythemal action spectrum and de­ oxyribonucleic acid repair synthesis in xeroderma pigmentosum. Br. 1. Der­ matol. 92:49-56 4. Burk, P. G., L utzner, M . A., Clarke, D. D., Robbins, J. H. 1 97 1 . U ltravi­ olet-stimulated thymidine incorpo­ ration in xeroderma pigmentosum lymphocytes. J. Lab. Clin. Med. 77: 759-67 5. Cleaver, J. E. 1972. Xeroderma pig­ mentosum: Variants with normal DNA repair and normal sensitivity to ultra­ violet light. J. Invest. Dermatol. 58: 124-28 6. Cleaver, 1. E., Carter, D. M. 1 973.

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Xeroderma pigmentosum variants: In­ fluence of temperature on DNA repair. J. In e t. Dermatol. 60:29-32 7. deSanctis, C, Cacchione, A. 1 932. L'idiozia xerodermica. Riv. Spero

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Freniatr. Med. Leg. Alienazioni Ment. 56:269-74 8. Reed, W. B., Landing, B., Sugarman, G., Cleaver, J. E., Melnyk, J. 1 969. Xeroderma pigmentosum: Clinical and laboratory mvestigation of its basic defect. J. Am. Med. Assoc. 207:2073-79 9. Ramsey, C. A., Coitart, T. M . , Blunt, S., Pawsey, S. A., Giannelli, F. 1 974. Prenatal diagnosis of xeroderma pig­ mentosum. Report of first successful case. Lancet 2: 109- 1 2 10. McKusick, V. A. 1 97 1 . Mendelian In­

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Cleaver, J. E. 1 975. Sister chromatid exchanges in xeroderma pigmentosum cells. Genetics. In press 12. German, J. 1 972. Genes which increase

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chromosomal instability in somatic cells and predispose to cancer. Prog. Med. Genel. 8:61- 1 0 1 W altimo, 0., Iivanainen, M., Hok­ kanen, E. 1967. Xeroderma pigmen­ tosum with neurological mantfesta­ tions. Family.studies of two affected sisters, one of them with a chromosome abnormality, and report of one separate case. Acta Neurol. Scand. 43: Supp!., 3 1 :66-67 Parrington, J. M., Delhanty, J. D. A., Baden, H. P. 1 97 1 . Unscheduled DNA synthesis, u.v.-induced chromosome aberrations and SV40 transformation in cultured cells from xeroderma pig­ mentosum. Ann. Hum. Genet. 35: 149-60 Sasaki, M. S. 1973. DNA repair capac­ ity and susceptibility to chromosome breakage in xeroderma pigmentosum cells. Mutat. Res. 20:29 1-93 Stich, H. F., San. R. H. C. 1 97 1 . Re­ duced DNA repair synthesis in xero­ derma pigmentosum cells exposed to the oncogenic 4-nitroquinoline I-oxide and4-hydroxyaminoquinoline I-oxide. Mutat. Res. 13:279-82 Jacobs, A J., O'Brien, R. L., Parker, J. W., Paolilli, P. 1 972. Abnormal DNA repair of 4-nitroquinoline-I-oxide-in­ duced damage by lymphocytes i n xeroderma pigmentosum. Mutat. Res. 16:420-24 Cleaver, J. E. 1 97 1 . Repair of alkylation damage in ultraviolet-sensitive (xero­ derma pigmentosum ) human cells. Mutat. Res. 1 2:453-62 Gartler, S. M. 1 964. Inborn errors of metabolism at the cell culture level. I n

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radiation sensitivity in human (xero­ derma pigmentosum) cells. Int. J. Ra­ dial. BioI. 1 8 : 557-65 Goldstein, S. 1 97 1 . The role of DNA repair in aging of cultured fibroblasts from xeroderma pigmentosum and normals. Proc. Soc. Exp. BioI. Med. 137: 730-34 Takebe, H., Furuyama. J-1.. Miki. Y.. Kondo, S. 1972. High sensitivity of xeroderma pigmentosum cells to the carcinogen 4-nitroquinoline-I-oxide. Mutat. Res. 1 5 :98- 1 00 Stich, H . F., San, R. H . c., Kawazoe, Y. 1973. Increased sensitivity of xero­ derma igmentosum cells to some chemica carcinogens and mutagens. Mutat. Res. 1 7 : 1 27-37 Stich, H. F., San, R. H. C. 1973. DNA

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repair synthesis and survival of repair deficient human cells exposed to the K-region epoxide of benz(a)anthra­ cene. Proc. Soc. Exp. Bioi. Med. 142: ISS-58 Maher, V. M., Birch, N., Otto, J. R .. McCormick, J. 1. 1975. Different cyto­ toxicity of derivatives of carcinogenic aromatic amides in normally repairing human skin fibroblasts and in xero­ derma pigmentosum strains with dif­ ferent capacities for DNA repair. J. Nat. Cancer Inst. In press Rabson, A. S., Tyrrell, S. A, Legallais, F. Y. 1 969. Growth of uftravi­ olet-damaged herpesvirus i n xero­ derma pigmentosum cells. Proc. Soc. Exp. BioI. Med. 1 3 2 : 802-6 Lytle, C. D., Aaronson, S. A., H arvey, E. 1 972. Host-cell reactivation III mammalian cells. I I. Survival by herpes simplex virus and vaccinia virus in normal human and xeroderma pig­ mentosum cells. Int. J. Radiat. BioI. 22: 1 59-65 Aaronson, S. A., Lytle, C. D. 1 970. Decreased host cell reactivation of ir­ radiated SV40 virus in xeroderma pig­ mentosum. Nature London 228:359-61 Day, R. S. I I I. 1974. Studies on repair of adenovirus 2 by human fibrobfasts using normal, xeroderma pigmento­ sum,· and xeroderma pigmentosum heterozygous strains. Cancer Res. 34: 1 965-70 Day, R. S. III. 1974. Cellular reactiva­ tion of ultraviolet-irradiated human adenovirus 2 in normal and xeroderma pigmentosum fibroblasts. Photochem.

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31. Zavadova, Z. 197 1 . Host-cell repair of vaccinia virus and of double stranded RNA of encephalomyocarditis virus. Nalure London New BioI. 233: 1 23 32. Day, R. S. I I I. 1 975. Xeroderma ig­ mentosum variants have decrease re­ pair of ultraviolet-damaged DNA. Na­ ture London. 253:748-49 33. Aaronson, S. A 1 970. Susceptibility of human cell strains to transformation by simian virus 40 and simian virus 40 deoxyribonucleic acid. J. Viral. 6:470-75 34. Veldhuisen, G., Pouwels, P. H. 1 970. Transformation of xeroderma pigmen­ tosum cells by SV40. Lancet 1:529-30 35. Key, D. J., Tadaro, G. J. 1 974. Xero­ derma pigmentosum cell susceptibility to SV40 virus transformation: Lack of effect of low dosage ultraviolet radia­ tion in enhancing viral-induced trans­ formation.J. Invest. Derm alol 62:7- 1 0

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36. Bootsma, D., Mulder, M. P., Pot, F., Cohen, J. A. 1 970. D ifferent inherited levels of DNA repair replicatiOIi. in xeroderma pigmentosum cell strains after exposure to ultraviolet irradiation.

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37. Cleaver, J. E. 1968. Defective repair replication of DNA in xeroderma pig­ mentosum. Nalure London 2 1 8 : 652-56 38. Cleaver, J. E. 1 969. Xeroderma pig­ mentosum: A human disease in which an initial stage of DNA repair is defec­ tive. Proc. Nal. A cad. Sci. USA 63:428-35 39. Setlow, R. B ., Regan, J. D., German, J., Carrier. W. L. 1 969. Evidence that xeroderma pigmentosum cells do not perform the first step in the repair of ultraviolet damage to their DNA. Proc. Nal. A cad Sci. USA 64: 1035-41 40. Cleaver, J. E., Trosko, J. E. 1 970. Ab­ sence of excision of ultraviolet-induced cyc\obutane dimers in xeroderma pig­ mentosum. Pholochem. Pholobiol.

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4 1 . Paterson, M. C, Lohman. P. H. Moo Sluyter, M. L . 1 973. Use of a UV en­ donuclease from Micrococcus luleus to monitor the progress of DNA repair in UV-irradiated human cells. Mulal. Res 1 9 : 245-56 42. Cleaver, J. E. 1974. Repair processes for photochemical damage III mam­ malian cells. A dv. Radial. Bioi. 4: 1 -75 43. Grossman. L. 1 974. Enzymes involved in the repair of DNA. A dv. Radial. BioI. 4:77- 129 44. Setlow, R. B. 1 967. Repair of DNA. I n Regulalion of Nucleic A cid and Pro­ tein Biosynthesis, ed. V. V . Konings­ berger, L. Bosch, 5 1 -62. Amsterdam : Elsevier 45. Kleijer, W. J., Hoeksema, J. L., Sluyter, M. L., Bootsma, D. 1973. Effects of inhibitors on repair of DN A in normal human and xeroderma pigmentosum cells after exposure to X-rays and ul­ traviolet irrad iation. Mulal. Res. 1 7 :385-94 46. Cleaver, J. E 1 974. Sedimentation of DNA from human fibroblasts irra­ diated with ultraviolet light : Possible detection of excision breaks in normal and repair-deficient xeroderma pig­ mentosum cells. Radial. Res. 57: 207-27 47. Cleaver, J. E, Thomas, G. H., Trosko, J. E., Lett, J. T. 1 972. Excision repair (dimer excision, strand breakage and repair replication) in primary cultures of cukaryotic (bovine) cells. Exp. Cell

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tivating enzyme. Proc. Nat. A cad. Sci. USA 72: \03-7 6 1 . Haynes, R. H. 1966. General discus­ sion. Radial. Res. Supp l. 6 : 232 62. Lehmann, A. R. et al 1975. Xeroderma pigmentosum cells with normal levels of excision repair have a defect in DNA synthesis after UV -irradiation. Proc.

Nat. A cad. Sci. USA 72 : 2 1 9-23 63. Cleaver, 1. E., Thomas, G. H. 1969.

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64. Meyn, R. E., Humphrey, R. M. 197 1 . Deoxyribonucleic acid synthesis i n ul­ t rav i o l e t - l i gh t - i r ra d i a t e d C h i n e s e hamster cells. Biophys. J. I I :295-301 65. Buhl, S. N., Setlow, R. B., Regan, 1. D. 1972. Steps in DNA chain elonga­

tion and joinmg after ultra-violet ir­ radiation of human cells. Int. J. Radial.

Bioi. 22:4 17-24 66. Buhl, S. N., Stillman, R. M., Setlow, R. B., Regan, J. D. 1972. DNA chain

elongation and joining i n normal human and xeroderma pigmentosum cells after ultraviolet irradiation. Biophys. J. 12: 1 1 83-9 1 67. ChlU, S. F. H., Rauth, A. M. 1972: Nascent DNA synthesis in ultraviolet light-irradiated mouse L cells. Biochim.

Biophys. A cla 259: 1 64-74 68. FUJ iwara, Y., Kondo, S. 1 972. Caf­

feine-sensitive repair of u l traviolet light-damaged DNA in mouse L cells.

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Cell Res. 75 :483-89 70. Lehmann, A. R. 1972. Postre pl i ca t i on repair of DNA in ultraviolet-irradiated mammalian cells. J. Mol. Bioi. 66:

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of caffeine on postreplication repair in human cells. Biophys. J. 14: 5 1 9 27 75. Lehmann, A. R., Kirk-Bell, S. 1 974. Effects of caffeine and theophylline on DNA synthesis in unirradiated and UV-irradiated mammalian cells. Mulal.

Res. 26:73-82 76. Cleaver, J . E. 1 969. Repair replication

of mammalian cell DNA: Effects of DNA syn thes i s or dark repair. Radial. Res. 37:334-48 77. Cleaver, J. E., Painter, R. B. 1 975. Absence uf specificity in inhibi tion of DNA repair replication by DNA bind­ ing agents, cocarcinogens, and steroids in human cells. Cancer Res. 3 5 : 1 1 73-78 78. Wilkinson, R., K iefer, 1., N ias, A. H . W . 1970. Effects o f post-t rea tmen t with caffeine on the sensitivity of ultraviolet light irradiation of two lines of HeLa cells. MUla!. Res. 10: 67-72 79. Goth, R., Cleaver, J. E. 1 975. Caf­ feine: A methyl donor and a precursor for purine metabolism. Radial. Res. compounds that inh i b i t

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1972. Excision repair: Our current knowledge based on human (xeroderma pigmentosu m ) cells. I n Ce7lular Repair Processes. ed. R. F. Beers, R. M. Herriott, R. C. Tilghman, 195-2 1 1 . Baltimore: Johns Ho pk i n s Univ. Press 8 1 . K le ijer, W. J . , Lohman, P. H . M . . Mulder, M . P . , Bootsma, D . 1 970. Re­ pair of X-ray damage in DNA of cul­ tivated cells from patients having xero­ derma pigmentosum. 9 : 5 1 7-23

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fective repair of N-acetoxy-2-acetyl­ aminoftuorene-induced lesions in the DNA of xeroderma pigmentosum cells.

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83. Stich, H. F., San, R. H. c., M iller. J. A., Miller, E . C. 1 972. Various levels of DNA repair sy nthesis in xeroderma

pigmentosum cells exposed to the car­ cinogens N-hydroxy and N -acetoxy2-acetylaminoftuorene. Nalure London

synthesized late after ultraviolet irra­ diation. Eur. J. Bioehem. 3 1 :438-45

New Bioi. 238 : 9 - 1 0 84. Cleaver, J. E. 1973. DNA repair with

size at long times after ultraviolet ir­

Cancer Res. 33: 362-69 85. Bresler, S. E., Kalinin, V. L., Sukhodo­ lova, A. T. 1972. Action of supermu­

72. Buhl, S. N . , Setlow, R. B., Regan, J. D. 1973. Recovery of the ability to synt hesi ze DNA in segments of normal radiation of human cells. Biophys. J. 1 3 : 1 265-75 73. Buh!, S. N., Setlow, R. B., Regan, J . D . 1 974. DNA repa i r i n Polorous Iri­ daelylus. Biophys. J. 1 4 : 7 9 1 -803 74. Buhl, S. N., Regan, J. D. 1974. Effect

purines and pyrimidines in radiation­ and can.:inugen-damaged nurmal and xeroderma pigmentosum human cells.

tagens on the transforming DNA of

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malian cells. In Genetic Concepts and Neoplasia. 593-600. Baltimore: Wil­ liams & Wilkins 87. Cleaver, 1. E. 1 975. Methods for study­ ing repai r of DNA damaged by p hys i ­

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