Direct involvement of retinoblastoma family proteins in DNA repair by non-homologous end-joining.
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Date
2015-03-31Author
Cook, R
Zoumpoulidou, G
Luczynski, MT
Rieger, S
Moquet, J
Spanswick, VJ
Hartley, JA
Rothkamm, K
Huang, PH
Mittnacht, S
Type
Journal Article
Metadata
Show full item recordAbstract
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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Subject
Humans
Genomic Instability
DNA Helicases
DNA-Binding Proteins
Retinoblastoma Protein
Tumor Suppressor Proteins
Antigens, Nuclear
Cell Cycle
Recombination, Genetic
DNA Breaks, Double-Stranded
DNA End-Joining Repair
Ku Autoantigen
Research team
Protein Networks
Molecular and Systems Oncology
Language
eng
Date accepted
2015-02-24
License start date
2015-03-26
Citation
Cell reports, 2015, 10 (12), pp. 2006 - 2018
Publisher
CELL PRESS