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PMID: 23055523 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

RING finger nuclear factor RNF168 is important for defects in homologous recombination caused by loss of the breast cancer susceptibility factor BRCA1.

The Journal of biological chemistry ·Vol. 287 ·No. 48 ·2012-11-23 ·Pages 40618-28

Muñoz MC, Laulier C, Gunn A, Cheng A, Robbiani DF, Nussenzweig A, Stark JM

Abstract

RNF168 promotes chromosomal break localization of 53BP1 and BRCA1; 53BP1 loss rescues homologous recombination (HR) in BRCA1-deficient cells. RNF168 depletion suppresses HR defects caused by BRCA1 silencing; RNF168 influences HR similarly to 53BP1. RNF168 is important for HR defects caused by BRCA1 loss. Although RNF168 promotes BRCA1 and 53BP1 localization to chromosomal breaks, RNF168 affects HR similarly to 53BP1. The RING finger nuclear factor RNF168 is required for recruitment of several DNA damage response factors to double strand breaks (DSBs), including 53BP1 and BRCA1. Because 53BP1 and BRCA1 function antagonistically during the DSB repair pathway homologous recombination (HR), the influence of RNF168 on HR has been unclear. We report that RNF168 depletion causes an elevated frequency of two distinct HR pathways (homology-directed repair and single strand annealing), suppresses defects in HR caused by BRCA1 silencing, but does not suppress HR defects caused by disruption of CtIP, RAD50, BRCA2, or RAD51. Furthermore, RNF168-depleted cells can form ionizing radiation-induced foci of the recombinase RAD51 without forming BRCA1 ionizing radiation-induced foci, indicating that this loss of BRCA1 recruitment to DSBs does not reflect a loss of function during HR. Additionally, we find that RNF168 and 53BP1 have a similar influence on HR. We suggest that RNF168 is important for HR defects caused by BRCA1 loss.

MeSH Terms
BRCA1 Protein/deficiency,genetics Breast Neoplasms/genetics,metabolism Cell Line, Tumor DNA Repair Female Gene Silencing Homologous Recombination Humans Intracellular Signaling Peptides and Proteins/genetics,metabolism RING Finger Domains Tumor Suppressor p53-Binding Protein 1 Ubiquitin-Protein Ligases/chemistry,genetics,metabolism
Chemicals
BRCA1 Protein Intracellular Signaling Peptides and Proteins TP53BP1 protein, human Tumor Suppressor p53-Binding Protein 1 RNF168 protein, human Ubiquitin-Protein Ligases
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Muñoz Meilen C
Department of Radiation Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
Laulier Corentin
Gunn Amanda
Cheng Anita
Robbiani Davide F
Nussenzweig André
Stark Jeremy M
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Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
1083-351X
DOI
10.1074/jbc.M112.410951
Published
2012-11-23
Epub
2012-00-10
Pages
40618-28
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC3504775
Subset
IM
Grants
NCI NIH HHS · R01 CA120954 · United States
NCI NIH HHS · R01CA120954 · United States
External Links
PubMed source DOI: 10.1074/jbc.M112.410951 PMC Full Text View journal details
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