Direct Involvement of Retinoblastoma Family Proteins in DNA Repair by Non-homologous End-Joining

Direct Involvement of Retinoblastoma Family Proteins in DNA Repair by Non-homologous End-Joining

Deficiencies in DNA double-strand break (DSB) repair lead to genetic instability, a recognized cause of cancer initiation and evolution. We report that the retinoblastoma tumor suppressor protein (RB1) is required for DNA DSB repair by canonical non-homologous end-joining (cNHEJ). Support of cNHEJ i...

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Main Authors: Cook, Rebecca, Zoumpoulidou, Georgia, Luczynski, Maciej T., Rieger, Simone, Moquet, Jayne, Spanswick, Victoria J., Hartley, John A., Rothkamm, Kai, Huang, Paul H., Mittnacht, Sibylle
Format: Online
Language:English
Published: Cell Press 2015
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4386026/
id pubmed-4386026
recordtype oai_dc
spelling pubmed-43860262015-04-13 Direct Involvement of Retinoblastoma Family Proteins in DNA Repair by Non-homologous End-Joining Cook, Rebecca Zoumpoulidou, Georgia Luczynski, Maciej T. Rieger, Simone Moquet, Jayne Spanswick, Victoria J. Hartley, John A. Rothkamm, Kai Huang, Paul H. Mittnacht, Sibylle Article Deficiencies in DNA double-strand break (DSB) repair lead to genetic instability, a recognized cause of cancer initiation and evolution. We report that the retinoblastoma tumor suppressor protein (RB1) is required for DNA DSB repair by canonical non-homologous end-joining (cNHEJ). Support of cNHEJ involves a mechanism independent of RB1’s cell-cycle function and depends on its amino terminal domain with which it binds to NHEJ components XRCC5 and XRCC6. Cells with engineered loss of RB family function as well as cancer-derived cells with mutational RB1 loss show substantially reduced levels of cNHEJ. RB1 variants disabled for the interaction with XRCC5 and XRCC6, including a cancer-associated variant, are unable to support cNHEJ despite being able to confer cell-cycle control. Our data identify RB1 loss as a candidate driver of structural genomic instability and a causative factor for cancer somatic heterogeneity and evolution. Cell Press 2015-03-26 /pmc/articles/PMC4386026/ /pubmed/25818292 http://dx.doi.org/10.1016/j.celrep.2015.02.059 Text en © 2015 The Authors http://creativecommons.org/licenses/by-nc-nd/3.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Cook, Rebecca
Zoumpoulidou, Georgia
Luczynski, Maciej T.
Rieger, Simone
Moquet, Jayne
Spanswick, Victoria J.
Hartley, John A.
Rothkamm, Kai
Huang, Paul H.
Mittnacht, Sibylle
spellingShingle Cook, Rebecca
Zoumpoulidou, Georgia
Luczynski, Maciej T.
Rieger, Simone
Moquet, Jayne
Spanswick, Victoria J.
Hartley, John A.
Rothkamm, Kai
Huang, Paul H.
Mittnacht, Sibylle
Direct Involvement of Retinoblastoma Family Proteins in DNA Repair by Non-homologous End-Joining
author_facet Cook, Rebecca
Zoumpoulidou, Georgia
Luczynski, Maciej T.
Rieger, Simone
Moquet, Jayne
Spanswick, Victoria J.
Hartley, John A.
Rothkamm, Kai
Huang, Paul H.
Mittnacht, Sibylle
author_sort Cook, Rebecca
title Direct Involvement of Retinoblastoma Family Proteins in DNA Repair by Non-homologous End-Joining
title_short Direct Involvement of Retinoblastoma Family Proteins in DNA Repair by Non-homologous End-Joining
title_full Direct Involvement of Retinoblastoma Family Proteins in DNA Repair by Non-homologous End-Joining
title_fullStr Direct Involvement of Retinoblastoma Family Proteins in DNA Repair by Non-homologous End-Joining
title_full_unstemmed Direct Involvement of Retinoblastoma Family Proteins in DNA Repair by Non-homologous End-Joining
title_sort direct involvement of retinoblastoma family proteins in dna repair by non-homologous end-joining
description Deficiencies in DNA double-strand break (DSB) repair lead to genetic instability, a recognized cause of cancer initiation and evolution. We report that the retinoblastoma tumor suppressor protein (RB1) is required for DNA DSB repair by canonical non-homologous end-joining (cNHEJ). Support of cNHEJ involves a mechanism independent of RB1’s cell-cycle function and depends on its amino terminal domain with which it binds to NHEJ components XRCC5 and XRCC6. Cells with engineered loss of RB family function as well as cancer-derived cells with mutational RB1 loss show substantially reduced levels of cNHEJ. RB1 variants disabled for the interaction with XRCC5 and XRCC6, including a cancer-associated variant, are unable to support cNHEJ despite being able to confer cell-cycle control. Our data identify RB1 loss as a candidate driver of structural genomic instability and a causative factor for cancer somatic heterogeneity and evolution.
publisher Cell Press
publishDate 2015
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4386026/
_version_ 1613207881213018112

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