DNA single-strand breaks (SSB) are the most common form of DNA damage, requiring repair processes that to initiate must overcome chromatin barriers. The FACT complex comprised of the SSRP1 and SPT16 proteins is important for maintaining chromatin integrity, with SSRP1 acting as an histone H2A/H2B chaperone in chromatin disassembly during DNA transcription, replication, and repair. In this study, we show that SSRP1, but not SPT16, is critical for cell survival after ionizing radiation or methyl methanesulfonate–induced single-strand DNA damage. SSRP1 is recruited to SSB in a PARP-dependent manner and retained at DNA damage sites by N-terminal interactions with the DNA repair protein XRCC1. Mutational analyses showed how SSRP1 function is essential for chromatin decondensation and histone H2B exchange at sites of DNA strand breaks, which are both critical to prime chromatin for efficient SSB repair and cell survival. By establishing how SSRP1 facilitates SSB repair, our findings provide a mechanistic rationale to target SSRP1 as a general approach to selectively attack cancer cells. Cancer Res; 77(10); 2674–85. ©2017 AACR.
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