期刊
MOLECULAR CELL
卷 77, 期 1, 页码 26-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2019.09.024
关键词
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资金
- NIH [R01CA197506, R01 227001]
- Ellison Medical Foundation Senior Scholar in Aging Award [AG-SS-2633-11]
- Department of Defense [W81XWH-15-2-006, W81XWH-16-1-599]
- Alex's Lemonade Stand Foundation Award
- NIH Intramural FLEX Award
- NATIONAL CANCER INSTITUTE [ZIABC010283, ZIABC010959, ZICBC010858] Funding Source: NIH RePORTER
53BP1 activity drives genome instability and lethality in BRCA1-deficient mice by inhibiting homologous recombination (HR). The anti-recombinogenic functions of 53BP1 require phosphorylation-dependent interactions with PTIP and RIF1/shieldin effector complexes. While RIF1/shieldin blocks 5'-3' nucleolytic processing of DNA ends, it remains unclear how PTIP antagonizes HR. Here, we show that mutation of the PTIP interaction site in 53BP1 (S25A) allows sufficient DNA2-dependent end resection to rescue the lethality of BRCAP(Delta 11) mice, despite increasing RIF1 end-blocking at DNA damage sites. However, double-mutant cells fail to complete HR, as excessive shieldin activity also inhibits RNF168-mediated loading of PALB2/RAD51. As a result, BRCA1(Delta 11)53BP1(S25A) mice exhibit hallmark features of HR insufficiency, including premature aging and hypersensitivity to PARPi. Disruption of shieldin or forced targeting of PALB2 to ssDNA in BRCA1(D1)(1)53BP1(S25A) cells restores RNF168 recruitment, RAD51 nucleofilament formation, and PARPi resistance. Our study therefore reveals a critical function of shieldin post-resection that limits the loading of RAD51.
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