Abstract
FANCJ helicase mutations are known to cause hereditary breast and ovarian cancers as well as bone marrow failure syndrome Fanconi anemia. FANCJ plays an important role in the repair of DNA inter-strand crosslinks and DNA double-strand breaks (DSBs) by homologous recombination (HR). Nonetheless, the molecular mechanism by which FANCJ controls HR mediated DSB repair is obscure. Here, we show that FANCJ promotes DNA end resection by recruiting CtIP to the sites of DSBs. This recruitment of CtIP is dependent on FANCJ K1249 acetylation. Notably, FANCJ acetylation is dependent on FANCJ S990 phosphorylation by CDK. The CDK mediated phosphorylation of FANCJ independently facilitates its interaction with BRCA1 at damaged DNA sites and promotes DNA end resection by CtIP recruitment. Strikingly, mutational studies reveal that ATP binding competent but hydrolysis deficient FANCJ partially supports end resection, indicating that in addition to the scaffolding role of FANCJ in CtIP recruitment, its helicase activity is important for promoting end resection. Together, these data unravel a novel function of FANCJ helicase in DNA end resection and provide mechanistic insights into its role in repairing DSBs by HR and in genome maintenance.
Highlights
DNA double-strand breaks (DSBs) are the most toxic form of DNA lesions that arise endogenously or by exposure to various chemicals and radiation
Cyclin-dependent kinases (CDKs) and various factors including MRE11, CtIP, EXO1, and BLM helicase participate in DNA end resection to promote homologous recombination (HR) mediated DSB repair
We show that FANCJ helicase controls DNA end resection by recruiting CtIP to the sites of DSBs
Summary
DNA double-strand breaks (DSBs) are the most toxic form of DNA lesions that arise endogenously or by exposure to various chemicals and radiation. Unrepaired or mis-repaired DSBs can lead to genome instability and tumorigenesis [1]. Defect in the repair of DSBs is associated with chromosome instability and cancer susceptibility genetic diseases including Fanconi anemia (FA), Bloom syndrome and Werner syndrome [2, 3]. There are two major pathways to repair DSBs: non-homologous end joining (NHEJ) and homologous recombination (HR). NHEJ mediated repair is DNA template-independent and occurs in all phases of the cell cycle, and is often error-prone. HR mediated DSB repair is mostly errorfree, requires homologous template DNA and is restricted to S and G2 phase. Sister chromatids serve as a template for repairing broken DNA; HR is considered as the most accurate pathway for repairing DSBs and maintaining genome integrity [4,5,6,7,8]
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