Molecular Cell

Previews The Maternal Side of Fanconi Anemia Sergio Ruiz1 and Oscar Fernandez-Capetillo1,* 1Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain *Correspondence: [email protected] http://dx.doi.org/10.1016/j.molcel.2014.08.029

Fanconi anemia is characterized by a higher sensitivity to DNA crosslinking agents, including aldehydes. In this issue of Molecular Cell, Oberbeck et al. (2014) reveal that detoxification of aldehydes by pregnant mothers contributes to limit the severity of the disease. Fanconi anemia (FA) is a heterogeneous genetic syndrome characterized by developmental defects in multiple organs, aplastic anemia during childhood, and eventual bone marrow failure (BMF), together with increased cancer occurrence, especially leukemia. This disease is caused by biallelic mutations in one of the sixteen genes (FANCA-Q) involved in a complex pathway of DNA repair. Specifically, FA cells are hypersensitive to DNA crosslinking agents, a feature that is used in vitro as a diagnostic hallmark. The disease is also associated with intrauterine dwarfism, suggesting that a stochastic fetal exposure to an endogenous and unknown genotoxic agent might already initiate the disease ab initio. Following on the previous studies from the Patel laboratory (Langevin et al., 2011; Rosado et al., 2011), Oberbeck et al. (2014) now show that both maternal and fetal ALDH2 are necessary in order to metabolize DNA damage-generating aldehydes in maturing FANCA-deficient embryos with life-long consequences (Figure 1A). A critical, and still unresolved, issue in the FA field resides in the identification of the primordial source of DNA damage that causes the disease. Although FAdeficient cells are hypersensitive to interstrand crosslinking agents, such as mitomycin C or cisplatin, these neither are environmental chemicals nor are produced in living organisms. A search for the endogenous source of DNA damage that causes FA identified aldehydes, known to generate DNA adducts, as a potential responsible agent. These highly reactive molecules not only are found in the environment but also are common byproducts of various metabolic routes, such as the catabolism of ethanol. Extensive work from the Patel laboratory has re-

vealed that the FA pathway counteracts the genotoxic effect of various reactive aldehydes. Studies in chicken DT40 cells showed that FA mutations confer sensitivity to formaldehyde and acetaldehyde (Langevin et al., 2011; Rosado et al., 2011). In addition, they observed that ALDH2, the main acetaldehyde-catabolizing enzyme, is essential for development of FANCD2-deficient mice (Langevin et al., 2011). This work was seminal since, in contrast to the situation in human patients, mice deficient in key FA genes such as FANCD2 or FANCA show a very modest phenotype, raising doubts about the conservation of the pathway. It is tempting to speculate that the discrepancies might lie on the capacity of each species to detoxify aldehydes, or on the chronological time to which each organism is exposed to the insult (humans live longer). These previous studies already hinted a contribution of the maternal ALDH2 to ameliorate the severity of FA (Langevin et al., 2011). Whereas Aldh2 / Fancd2 / mice were early embryonic lethal when the mother was deficient for ALDH2, double-knockout pups were born from Aldh2 heterozygous mothers. This result suggested that the ability of the mother to catabolize aldehydes influenced the development of Aldh2 / Fancd2 / embryos in utero. Now, the authors explored this phenomenon in depth. Importantly, the current study is based on FANCA, the mutation that shows the highest prevalence (60%) in human patients. By a series of elegant crosses they observed that, in contrast to what they previously reported for FANCD2, Aldh2 / Fanca / mice were embryonic lethal regardless of the maternal Aldh2 status (Figure 1A). Moreover, Aldh2+/ Fanca / mice were not born at the expected ratio, revealing

a haploinsufficient activity of ALDH2. This result is highly relevant due to the abundance of Aldh2 mutation carriers, particularly on the Asian population (see below). Interestingly, ALDH2 deficiency has a more profound effect on Fanca / than on Fancd2 / mice. FANCA is a component of the FA core that initiates the repair of DNA crosslinks through a pathway that is thought to converge on the ubiquitinylation of FANCD2. However, the results presented here suggest that the FA core might target additional proteins besides FANCD2. Of note, and in contrast to its effect on FANCA or FANCD2, REV1 / mice are not affected by ALDH2 deficiency and, thus, REV1 seems to be dispensable for the response to reactive aldehydes. REV1 is a component of translation synthesis that participates, in cooperation with FA proteins, in the repair of crosslinks initiated by chemotherapeutic agents (Knipscheer et al., 2009). One interesting possibility to explain this discrepancy might relate to the fact that aldehydes also promote strong protein crosslinks, yet further studies would be needed to clarify this discrepancy. As a formal demonstration of the maternal contribution to FA phenotypes, the authors show that the lethality of Aldh2 / Fanca / embryos can be rescued by transferring them into ALDH2-proficient mothers (Figure 1A). This demonstrates that maternal acetaldehyde catabolism is necessary and sufficient to allow double mutant mice to proceed through embryogenesis. Moreover, biochemical assays reveal that mouse embryos and placenta show a very reduced ALDH activity when compared to that observed on maternal livers. Regardless of the maternal contribution, born Aldh2 / Fanca / mice still

Molecular Cell 55, September 18, 2014 ª2014 Elsevier Inc. 803

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to stimulate not only wild-type but also mutant ALDH2 (Chen et al., 2008), in FA patients or in situations where acetaldehyde levels might spike such as alcoholism or in ALDH2*2 carriers (Figure 1B). The lasting influence of the embryonic period on the future onset of disease is known as ‘‘intrauterine programming’’ and has been previously documented on other DNA damage-triggered syndromes such as ATR-Seckel (Murga et al., 2009). Oberbeck et al. (2014) now reveal that the genetic background of the mother can contribute to this phenomenon, by modulating the levels of endogenous DNA damage-generating metabolites in the developing embryo. To what extent this opens the door for a therapeutic intervention remains to be seen, but, if it is to come, it should always be kept in mind how the disease, as well as the patient, were ‘‘born.’’

A

B

Figure 1. Exploring the Role of Aldehydes on the Development of Fanconi Anemia (A) Absence of maternal ALDH2 leads to the accumulation of reactive aldehydes, which limit the viability of FANCA-deficient mice. When Aldh2 / Fanca / embryos are transferred into an ALDH2-proficient mother, they proceed through embryogenesis and even reach adulthood although eventually succumb to BMF. Hence, both maternal and fetal ALDH2 activity contributes to suppress the severity of FA in mice. (B) Through their genotoxic effects, reactive aldehydes have been involved in the genesis of FA, alcoholrelated pathologies, and cancer. Stimulating ALDH2 through agonists (e.g., Alda-1) could potentially mitigate the severity of these effects. Regardless of aldehydes, it remains possible that other endogenous metabolites capable of inducing DNA crosslinks are also involved in the pathogenesis of FA.

showed severe developmental defects and a profound attrition in the hematopoietic stem cell (HSC) pool, further reinforcing the idea that HSC are particularly sensitive toward aldehyde-mediated DNA damage (Ceccaldi et al., 2012; Garaycoechea et al., 2012). An important corollary to this work is the potential impact of ALDH2 mutations on human disease (Figure 1B). More than 500 million individuals worldwide, and almost half of the Japanese population, carry a dominant-negative mutation in ALDH2 (ALDH2*2). Interestingly, this ALDH2 variant is associated with a faster progression of BMF in FA patients (Hira et al., 2013). Furthermore, ALDH2*2 carrying individuals are easily recognizable by the alcohol facial flushing response, a characteristic physiological symptom derived from the ingestion of alcohol. In fact, ethanol is first metabolized into acetaldehyde, the main substrate for ALDH2.

Whereas no obvious FA symptoms are observed on ALDH2 mutant mice or humans, a casual relationship between alcohol consumption and esophageal cancer has been reported in ALDH2*2 carriers (Brooks et al., 2009). Of note, acetaldehyde levels in saliva are 10–20 times higher than in blood due to the metabolism of the oral microbiota, which could account for the esophageal bias. Whereas the current results support that reactive aldehydes worsen FA phenotypes in mammals, it remains to be seen whether these compounds are the true endogenous insult that triggers FA (Figure 1B). To formally prove that aldehydes are the bona fide genotoxin in FA, it would be necessary to show that lowering the physiological levels of aldehydes in vivo is able to limit the severity of the disease. In this context, it might be worth considering the use of ALDH2 agonists such as Alda-1, a molecule able

804 Molecular Cell 55, September 18, 2014 ª2014 Elsevier Inc.

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The maternal side of Fanconi Anemia.

Fanconi anemia is characterized by a higher sensitivity to DNA crosslinking agents, including aldehydes. In this issue of Molecular Cell, Oberbeck et ...
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