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


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.

SUBMITTER: Cook R 

PROVIDER: S-EPMC4386026 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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

Cook Rebecca R   Zoumpoulidou Georgia G   Luczynski Maciej T MT   Rieger Simone S   Moquet Jayne J   Spanswick Victoria J VJ   Hartley John A JA   Rothkamm Kai K   Huang Paul H PH   Mittnacht Sibylle S  

Cell reports 20150326 12


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 fu  ...[more]

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