CPSF6 通过稳定 RAD52 并促进 CHK1 激活维持基因组稳定性
CPSF6 maintains genomic stability by stabilizing RAD52 and promoting CHK1 activation
CPSF6 被鉴定为一种新的 DNA 损伤应答（DDR）因子，通过稳定 RAD52 和促进 CHK1 激活维持基因组稳定性。机制上，CPSF6 与 RAD52 竞争性结合，阻止 E3 泛素连接酶 UHRF1 与 RAD52 相互作用及其随后的蛋白酶体降解；同时 CPSF6 增强 ATR–CHK1 互作以促进 CHK1 激活，进而启动下游 CHK1–PLK1–RAD51 通路。这两项功能共同支持 CPSF6 在转录–复制冲突（TRC）解析中的作用，CPSF6 缺失会导致 R-loop 积累和转录相关 DNA 损伤。
来源：Nucleic Acids Research · doi.org
RAD52 and CHK1 are critical factors that play pleiotropic roles in the DNA damage response (DDR), including the resolution of transcription–replication conflicts (TRCs). However, how their functions are modulated remains incomplete. Here, we reveal that the cleavage and polyadenylation specificity factor subunit 6 (CPSF6) is an unexpected DDR factor that enhances RAD52 stability and CHK1 activation. Specifically, CPSF6 competitively interacts with RAD52, thereby preventing RAD52 from interacting with the E3 ubiquitin ligase UHRF1 and subsequent proteasomal degradation. In addition, CPSF6 enhances the ATR–CHK1 interaction to promote CHK1 activation, thereby facilitating the activation of downstream CHK1–PLK1–RAD51 pathway. The dual functions of CPSF6 in RAD52 stabilization and CHK1 activation contribute to its role in TRC resolution. CPSF6 depletion causes R-loop accumulation and transcription-associated DNA damage. Notably, these roles of CPSF6 in the DDR are independent of its canonical role in pre-mRNA 3′-end processing. Collectively, our findings establish that CPSF6 is a novel factor critical for maintaining genomic stability, with the resolution of TRCs as an important mechanism.