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RB localizes to DNA double-strand breaks and promotes DNA end resection and homologous recombination through the recruitment of BRG1
The retinoblastoma (RB) tumor suppressor is recognized as a master regulator that controls entry into the S phase of the cell cycle. Its loss leads to uncontrolled cell proliferation and is a hallmark of cancer. RB works by binding to members of the E2F family of transcription factors and recruiting...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5159665/ https://www.ncbi.nlm.nih.gov/pubmed/27940962 http://dx.doi.org/10.1101/gad.288282.116 |
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author | Vélez-Cruz, Renier Manickavinayaham, Swarnalatha Biswas, Anup K. Clary, Regina Weaks Premkumar, Tolkappiyan Cole, Francesca Johnson, David G. |
author_facet | Vélez-Cruz, Renier Manickavinayaham, Swarnalatha Biswas, Anup K. Clary, Regina Weaks Premkumar, Tolkappiyan Cole, Francesca Johnson, David G. |
author_sort | Vélez-Cruz, Renier |
collection | PubMed |
description | The retinoblastoma (RB) tumor suppressor is recognized as a master regulator that controls entry into the S phase of the cell cycle. Its loss leads to uncontrolled cell proliferation and is a hallmark of cancer. RB works by binding to members of the E2F family of transcription factors and recruiting chromatin modifiers to the promoters of E2F target genes. Here we show that RB also localizes to DNA double-strand breaks (DSBs) dependent on E2F1 and ATM kinase activity and promotes DSB repair through homologous recombination (HR), and its loss results in genome instability. RB is necessary for the recruitment of the BRG1 ATPase to DSBs, which stimulates DNA end resection and HR. A knock-in mutation of the ATM phosphorylation site on E2F1 (S29A) prevents the interaction between E2F1 and TopBP1 and recruitment of RB, E2F1, and BRG1 to DSBs. This knock-in mutation also impairs DNA repair, increases genomic instability, and renders mice hypersensitive to IR. Importantly, depletion of RB in osteosarcoma and breast cancer cell lines results in sensitivity to DNA-damaging drugs, which is further exacerbated by poly-ADP ribose polymerase (PARP) inhibitors. We uncovered a novel, nontranscriptional function for RB in HR, which could contribute to genome instability associated with RB loss. |
format | Online Article Text |
id | pubmed-5159665 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-51596652017-05-15 RB localizes to DNA double-strand breaks and promotes DNA end resection and homologous recombination through the recruitment of BRG1 Vélez-Cruz, Renier Manickavinayaham, Swarnalatha Biswas, Anup K. Clary, Regina Weaks Premkumar, Tolkappiyan Cole, Francesca Johnson, David G. Genes Dev Research Paper The retinoblastoma (RB) tumor suppressor is recognized as a master regulator that controls entry into the S phase of the cell cycle. Its loss leads to uncontrolled cell proliferation and is a hallmark of cancer. RB works by binding to members of the E2F family of transcription factors and recruiting chromatin modifiers to the promoters of E2F target genes. Here we show that RB also localizes to DNA double-strand breaks (DSBs) dependent on E2F1 and ATM kinase activity and promotes DSB repair through homologous recombination (HR), and its loss results in genome instability. RB is necessary for the recruitment of the BRG1 ATPase to DSBs, which stimulates DNA end resection and HR. A knock-in mutation of the ATM phosphorylation site on E2F1 (S29A) prevents the interaction between E2F1 and TopBP1 and recruitment of RB, E2F1, and BRG1 to DSBs. This knock-in mutation also impairs DNA repair, increases genomic instability, and renders mice hypersensitive to IR. Importantly, depletion of RB in osteosarcoma and breast cancer cell lines results in sensitivity to DNA-damaging drugs, which is further exacerbated by poly-ADP ribose polymerase (PARP) inhibitors. We uncovered a novel, nontranscriptional function for RB in HR, which could contribute to genome instability associated with RB loss. Cold Spring Harbor Laboratory Press 2016-11-15 /pmc/articles/PMC5159665/ /pubmed/27940962 http://dx.doi.org/10.1101/gad.288282.116 Text en © 2016 Vélez-Cruz et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/. |
spellingShingle | Research Paper Vélez-Cruz, Renier Manickavinayaham, Swarnalatha Biswas, Anup K. Clary, Regina Weaks Premkumar, Tolkappiyan Cole, Francesca Johnson, David G. RB localizes to DNA double-strand breaks and promotes DNA end resection and homologous recombination through the recruitment of BRG1 |
title | RB localizes to DNA double-strand breaks and promotes DNA end resection and homologous recombination through the recruitment of BRG1 |
title_full | RB localizes to DNA double-strand breaks and promotes DNA end resection and homologous recombination through the recruitment of BRG1 |
title_fullStr | RB localizes to DNA double-strand breaks and promotes DNA end resection and homologous recombination through the recruitment of BRG1 |
title_full_unstemmed | RB localizes to DNA double-strand breaks and promotes DNA end resection and homologous recombination through the recruitment of BRG1 |
title_short | RB localizes to DNA double-strand breaks and promotes DNA end resection and homologous recombination through the recruitment of BRG1 |
title_sort | rb localizes to dna double-strand breaks and promotes dna end resection and homologous recombination through the recruitment of brg1 |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5159665/ https://www.ncbi.nlm.nih.gov/pubmed/27940962 http://dx.doi.org/10.1101/gad.288282.116 |
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