53BP1 Enforces Distinct Pre- and Post-resection Blocks on Homologous Recombination.
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&#...
| Autores: | , , , , , , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2020 |
| País: | España |
| Institución: | Instituto de Salud Carlos III (ISCIII) |
| Repositorio: | Repisalud |
| Idioma: | inglés |
| OAI Identifier: | oai:repisalud.isciii.es:20.500.12105/18185 |
| Acceso en línea: | http://hdl.handle.net/20.500.12105/18185 |
| Access Level: | acceso abierto |
| Palabra clave: | Aging Animals BRCA1 Protein DNA Breaks, Double-Stranded DNA Damage Genomic Instability Homologous Recombination Mice Mutation Poly(ADP-ribose) Polymerase Inhibitors Rad51 Recombinase Tumor Suppressor p53-Binding Protein 1 Ubiquitin-Protein Ligases |
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oai:repisalud.isciii.es:20.500.12105/18185 |
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53BP1 Enforces Distinct Pre- and Post-resection Blocks on Homologous Recombination.Callen, ElsaZong, DaliWu, WeiWong, NancyStanlie, AndreIshikawa, MomokoPavani, RaphaelDumitrache, Lavinia CByrum, Andrea KMendez-Dorantes, CarlosMartinez, PaulaCanela, AndresMaman, YaakovDay, AmandaKruhlak, Michael JBlasco, MAStark, Jeremy MMosammaparast, NimaMcKinnon, Peter JNussenzweig, AndréAgingAnimalsBRCA1 ProteinDNA Breaks, Double-StrandedDNA DamageGenomic InstabilityHomologous RecombinationMiceMutationPoly(ADP-ribose) Polymerase InhibitorsRad51 RecombinaseTumor Suppressor p53-Binding Protein 1Ubiquitin-Protein Ligases53BP1 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.Cell PressUnited States Department of Health and Human ServicesUnited States Department of DefenseLawrence Ellison Foundation20242024-02-1320202020-01-0220202020-01-02journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfapplication/pdfapplication/vnd.openxmlformats-officedocument.spreadsheetml.sheethttp://hdl.handle.net/20.500.12105/18185reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/181852026-06-12T12:43:37Z |
| dc.title.none.fl_str_mv |
53BP1 Enforces Distinct Pre- and Post-resection Blocks on Homologous Recombination. |
| title |
53BP1 Enforces Distinct Pre- and Post-resection Blocks on Homologous Recombination. |
| spellingShingle |
53BP1 Enforces Distinct Pre- and Post-resection Blocks on Homologous Recombination. Callen, Elsa Aging Animals BRCA1 Protein DNA Breaks, Double-Stranded DNA Damage Genomic Instability Homologous Recombination Mice Mutation Poly(ADP-ribose) Polymerase Inhibitors Rad51 Recombinase Tumor Suppressor p53-Binding Protein 1 Ubiquitin-Protein Ligases |
| title_short |
53BP1 Enforces Distinct Pre- and Post-resection Blocks on Homologous Recombination. |
| title_full |
53BP1 Enforces Distinct Pre- and Post-resection Blocks on Homologous Recombination. |
| title_fullStr |
53BP1 Enforces Distinct Pre- and Post-resection Blocks on Homologous Recombination. |
| title_full_unstemmed |
53BP1 Enforces Distinct Pre- and Post-resection Blocks on Homologous Recombination. |
| title_sort |
53BP1 Enforces Distinct Pre- and Post-resection Blocks on Homologous Recombination. |
| dc.creator.none.fl_str_mv |
Callen, Elsa Zong, Dali Wu, Wei Wong, Nancy Stanlie, Andre Ishikawa, Momoko Pavani, Raphael Dumitrache, Lavinia C Byrum, Andrea K Mendez-Dorantes, Carlos Martinez, Paula Canela, Andres Maman, Yaakov Day, Amanda Kruhlak, Michael J Blasco, MA Stark, Jeremy M Mosammaparast, Nima McKinnon, Peter J Nussenzweig, André |
| author |
Callen, Elsa |
| author_facet |
Callen, Elsa Zong, Dali Wu, Wei Wong, Nancy Stanlie, Andre Ishikawa, Momoko Pavani, Raphael Dumitrache, Lavinia C Byrum, Andrea K Mendez-Dorantes, Carlos Martinez, Paula Canela, Andres Maman, Yaakov Day, Amanda Kruhlak, Michael J Blasco, MA Stark, Jeremy M Mosammaparast, Nima McKinnon, Peter J Nussenzweig, André |
| author_role |
author |
| author2 |
Zong, Dali Wu, Wei Wong, Nancy Stanlie, Andre Ishikawa, Momoko Pavani, Raphael Dumitrache, Lavinia C Byrum, Andrea K Mendez-Dorantes, Carlos Martinez, Paula Canela, Andres Maman, Yaakov Day, Amanda Kruhlak, Michael J Blasco, MA Stark, Jeremy M Mosammaparast, Nima McKinnon, Peter J Nussenzweig, André |
| author2_role |
author author author author author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
United States Department of Health and Human Services United States Department of Defense Lawrence Ellison Foundation |
| dc.subject.none.fl_str_mv |
Aging Animals BRCA1 Protein DNA Breaks, Double-Stranded DNA Damage Genomic Instability Homologous Recombination Mice Mutation Poly(ADP-ribose) Polymerase Inhibitors Rad51 Recombinase Tumor Suppressor p53-Binding Protein 1 Ubiquitin-Protein Ligases |
| topic |
Aging Animals BRCA1 Protein DNA Breaks, Double-Stranded DNA Damage Genomic Instability Homologous Recombination Mice Mutation Poly(ADP-ribose) Polymerase Inhibitors Rad51 Recombinase Tumor Suppressor p53-Binding Protein 1 Ubiquitin-Protein Ligases |
| description |
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. |
| publishDate |
2020 |
| dc.date.none.fl_str_mv |
2020 2020-01-02 2020 2020-01-02 2024 2024-02-13 |
| dc.type.none.fl_str_mv |
journal article http://purl.org/coar/resource_type/c_6501 VoR http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/20.500.12105/18185 |
| url |
http://hdl.handle.net/20.500.12105/18185 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.rights.none.fl_str_mv |
open access http://purl.org/coar/access_right/c_abf2 Attribution-NonCommercial-NoDerivatives 4.0 Internacional http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| dc.rights.openaire.fl_str_mv |
info:eu-repo/semantics/openAccess |
| rights_invalid_str_mv |
open access http://purl.org/coar/access_right/c_abf2 Attribution-NonCommercial-NoDerivatives 4.0 Internacional http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| eu_rights_str_mv |
openAccess |
| dc.format.none.fl_str_mv |
application/pdf application/pdf application/vnd.openxmlformats-officedocument.spreadsheetml.sheet |
| dc.publisher.none.fl_str_mv |
Cell Press |
| publisher.none.fl_str_mv |
Cell Press |
| dc.source.none.fl_str_mv |
reponame:Repisalud instname:Instituto de Salud Carlos III (ISCIII) |
| instname_str |
Instituto de Salud Carlos III (ISCIII) |
| reponame_str |
Repisalud |
| collection |
Repisalud |
| repository.name.fl_str_mv |
|
| repository.mail.fl_str_mv |
|
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1869405865882157056 |
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15,812429 |