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Cell Rep. 2015 Mar 31;10(12):2006-18. doi: 10.1016/j.celrep.2015.02.059. Epub 2015 Mar 26.

Direct involvement of retinoblastoma family proteins in DNA repair by non-homologous end-joining.

Author information

1
Division of Cancer Biology, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK; Cancer Cell Signalling, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
2
Cancer Cell Signalling, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
3
Division of Cancer Biology, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
4
Public Health England, Centre for Radiation, Chemical and Environmental Hazards, Chilton, Didcot OX11 0RQ, UK.
5
Cancer Research UK Drug-DNA Interactions Research Group, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
6
Division of Cancer Biology, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK. Electronic address: paul.huang@icr.ac.uk.
7
Division of Cancer Biology, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK; Cancer Cell Signalling, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK. Electronic address: s.mittnacht@ucl.ac.uk.

Abstract

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.

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PMID:
25818292
PMCID:
PMC4386026
DOI:
10.1016/j.celrep.2015.02.059
[Indexed for MEDLINE]
Free PMC Article

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