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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...

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Autores principales: Vélez-Cruz, Renier, Manickavinayaham, Swarnalatha, Biswas, Anup K., Clary, Regina Weaks, Premkumar, Tolkappiyan, Cole, Francesca, Johnson, David G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2016
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.
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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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