Journal of Biological Chemistry
Journal of Biological Chemistry
5 years ago

Constitutive role of the Fanconi anemia D2 gene in the replication stress response.

Li, Klages-Mundt, Chen, Gao, Martin, Tian, Wang, Shen, Lynn, Schlacher, Ye
In response to DNA crosslinking damage, the Fanconi anemia (FA) core complex activates the FA pathway by monoubiquitinating Fanconi anemia complementation group D2 (FANCD2) for the initiation of the nucleolytic processing of the DNA crosslinks and stabilization of stalled replication forks. Given that all the classic FA proteins coordinately monoubiquitinate FANCD2, it is unclear why losses of individual classic FA genes yield varying cellular sensitivities to crosslinking damage. To address this question, we generated cellular knockout models of FA core complex components and FANCD2 and found that FANCD2-null mutants display higher levels of spontaneous chromosomal damage and hypersensitivity to replication-blocking lesions than Fanconi anemia complementation group L (FANCL)-null mutants, suggesting that FANCD2 provides a basal level of DNA protection countering endogenous lesions in the absence of monoubiquitination. FANCD2's ubiquitination-independent function is likely involved in optimized recruitment of nucleolytic activities for the processing and protection of stressed replication forks. Our results reveal that FANCD2 has an ubiquitination-independent role in countering endogenous levels of replication stress, a function that is critical for the maintenance of genomic stability.

Publisher URL: http://doi.org/10.1074/jbc.M117.814780

DOI: 10.1074/jbc.M117.814780

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