Lens epithelium-derived growth factor p75 splice variant (LEDGF) is a chromatin-binding protein known for its antiapoptotic activity and ability to direct human immunodeficiency virus into active transcription units. Here we show that LEDGF promotes the repair of DNA double-strand breaks (DSBs) by the homologous recombination repair pathway. Depletion of LEDGF impairs the recruitment of C-terminal binding protein interacting protein (CtIP) to DNA DSBs and the subsequent CtIP-dependent DNA-end resection. LEDGF is constitutively associated with chromatin through its Pro-Trp-Trp-Pro (PWWP) domain that binds preferentially to epigenetic methyl-lysine histone markers characteristic of active transcription units. LEDGF binds CtIP in a DNA damage-dependent manner, thereby enhancing its tethering to the active chromatin and facilitating its access to DNA DSBs. These data highlight the role of PWWP-domain proteins in DNA repair and provide a molecular explanation for the antiapoptotic and cancer cell survival-activities of LEDGF.
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Article Synopsis
- Double-strand breaks (DSBs) are harmful DNA lesions that threaten genomic stability, requiring efficient repair processes like nonhomologous end-joining (NHEJ) and homology-directed repair (HDR).
- The study investigates the roles of two proteins, DmCtIP and DmRif1, in Drosophila melanogaster (fruit flies) and finds that both are important for DSB repair, but with DmCtIP being the more critical protein.
- Experimental results show that when both proteins are absent, the DSB repair mechanisms (HR and SSA) are significantly impaired, indicating that DmCtIP leads the repair process rather than working redundantly with DmRif1.
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