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

被引：67

作者：

Cook, Rebecca ^{[1
,2
]}

Zoumpoulidou, Georgia ^{[2
]}

Luczynski, Maciej T. ^{[1
]}

Rieger, Simone ^{[2
]}

Moquet, Jayne ^{[4
]}

Spanswick, Victoria J. ^{[3
]}

Hartley, John A. ^{[3
]}

Rothkamm, Kai ^{[4
]}

Huang, Paul H. ^{[1
]}

Mittnacht, Sibylle ^{[1
,2
]}

机构：

[1] Inst Canc Res, Div Canc Biol, London SW3 6JB, England

[2] UCL, UCL Canc Inst, Canc Cell Signalling, London WC1E 6DD, England

[3] UCL, UCL Canc Inst, Canc Res UK Drug DNA Interact Res Grp, London WC1E 6DD, England

[4] Publ Hlth England, Ctr Radiat Chem & Environm Hazards, Didcot OX11 0RQ, Oxon, England

来源：

CELL REPORTS | 2015年 / 10卷 / 12期

基金：

英国惠康基金;

关键词：

STRAND BREAK REPAIR; TUMOR-SUPPRESSOR PROTEIN; AMINO-TERMINAL DOMAIN; GENOMIC INSTABILITY; HEMATOPOIETIC STEM; HEREDITARY RETINOBLASTOMA; HOMOLOGOUS RECOMBINATION; DAMAGE RESPONSE; PATHWAY CHOICE; GENE FAMILY;

D O I：

10.1016/j.celrep.2015.02.059

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

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.

引用

页码：2006 / 2018

页数：13

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