53BP1 Enforces Distinct Pre- and Post-resection Blocks on Homologous Recombination
| Autor: | Jeremy M. Stark, Andrea K. Byrum, Elsa Callen, Nancy Wong, Andre Stanlie, Yaakov Maman, Nima Mosammaparast, Raphael Souza Pavani, Michael J. Kruhlak, Amanda Day, Wei Wu, André Nussenzweig, Lavinia C. Dumitrache, Peter J. McKinnon, Dali Zong, Andres Canela, Maria A. Blasco, Carlos Mendez-Dorantes, Paula Martinez, Momoko Ishikawa |
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| Rok vydání: | 2020 |
| Předmět: |
Premature aging
Genome instability Aging DNA damage Ubiquitin-Protein Ligases RAD51 Poly(ADP-ribose) Polymerase Inhibitors Biology medicine.disease_cause Article Genomic Instability Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine medicine Animals DNA Breaks Double-Stranded Homologous Recombination Molecular Biology 030304 developmental biology 0303 health sciences Mutation BRCA1 Protein Effector Cell Biology Cell biology chemistry Rad51 Recombinase Tumor Suppressor p53-Binding Protein 1 Homologous recombination 030217 neurology & neurosurgery DNA DNA Damage |
| Zdroj: | Mol Cell |
| ISSN: | 1097-2765 |
| Popis: | Summary 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 BRCA1Δ11 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, BRCA1Δ1153BP1S25A 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 BRCA1D1153BP1S25A 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. |
| Databáze: | OpenAIRE |
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