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Review
. 2008 Aug;117(4):305-17.
doi: 10.1007/s00412-008-0154-8. Epub 2008 Mar 28.

Recognition of DNA double strand breaks by the BRCA1 tumor suppressor network

Roger A Greenberg  1
Affiliations
Review

Recognition of DNA double strand breaks by the BRCA1 tumor suppressor network

Roger A Greenberg. Chromosoma. 2008 Aug.

Abstract

DNA double-strand breaks (DSBs) occur in response to both endogenous and exogenous genotoxic stress. Inappropriate repair of DSBs can lead to either loss of viability or to chromosomal alterations that increase the likelihood of cancer development. In strong support of this assertion, many cancer predisposition syndromes stem from germline mutations in genes involved in DNA DSB repair. Among the most prominent of such tumor suppressor genes are the Breast Cancer 1 and Breast Cancer 2 genes (BRCA1 and BRCA2), which are mutated in familial forms of breast and ovarian cancer. Recent findings implicate BRCA1 as a central component of several distinct macromolecular protein complexes, each dedicated to distinct elements of DNA DSB repair and tumor suppression. Emerging evidence has shed light on some of the molecular recognition processes that are responsible for targeting BRCA1 and its associated partners to DNA and chromatin directly flanking DSBs. These events are required for BRCA1-dependent DNA repair and tumor suppression. Thus, a detailed temporal and spatial knowledge of how breaks are recognized and repaired has profound implications for understanding processes related to the genesis of malignancy and to its treatment.

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Figures

Fig. 1
Fig. 1
Models for DSB repair and for recognition of different DSB regions by repair proteins. a DNA DSBs can be repaired by either homologous recombination or non-homologous end joining mechanisms. Homologous recombination proceeds by a series of depicted DNA processing events to allow repair of a DSB by copying of the homologous region on the sister chromatid. Non-homologous end joining can repair DSBs by ligating contiguous (red or blue) stretches of DNA or non-contiguous regions (red and blue), resulting in chromosomal translocations. b Several different regions exist at the site of a DNA DSB. Nucleosomal clearing occurs directly adjacent to the DSB, followed by long stretches of chromatin modifications characterized by γH2AX-MDC1. BRCA1-BARD1 heterodimers accumulate at both the DNA and chromatin regions at DSB sites. BRCA1-BARD1 DSB chromatin accumulation is dependent on γH2AX-MDC1. Ubiquitin chains are also abundant at chromatin regions flanking DSBs
Fig. 2
Fig. 2
The BRCA1 tumor suppressor network. a Domain structure of the BRCA1-BARD1 heterodimer. Characteristic domains for BRCA1 include the amino terminal RING domain, Exon 11 region, and the BRCT domains. Loss of function, cancer predisposing mutations occur in each of these domains. b BRCA1 supercomplexes displaying characteristic, unique binding partners. A schematic is shown that displays DSB recognition elements and repair activities for each BRCA1-BARD1 containing complex in the DNA damage response
Fig. 3
Fig. 3
Model for the role of ubiquitin dynamics in BRCA1-directed DSB repair. RNF8-Ubc13 synthesizes K63-Ub on chromatin-associated substrates at DSB sites in a manner dependent on γH2AX-MDC1. Rap80 binds DSB-associated K63-Ub to target the BRCA1-BARD1 E3 Ub ligase and the BRCC36 DUB to DSBs. RNF8-Ubc13-dependent ubiquitination is also required for 53BP1 DSB recruitment. These opposing Ub synthesizing and degrading activities by RNF8-Ubc13 and Rap80-BRCC36, respectively, may alter ubiquitination events and chromatin structure to influence appropriate DSB repair. Alternatively, Rap80-BRCC36 DUB activity may represent a negative feedback mechanism to terminate RNF8-Ubc13 recruitment signals
See this image and copyright information in PMC

References

    1. Bassing CH, Chua KF, Sekiguchi J, Suh H, Whitlow SR, Fleming JC, Monroe BC, Ciccone DN, Yan C, Vlasakova K, Livingston DM, Ferguson DO, Scully R, Alt FW. Increased ionizing radiation sensitivity and genomic instability in the absence of histone H2AX. Proc Natl Acad Sci U S A. 2002;99(12):8173–8178. - PMC - PubMed
    1. Bekker-Jensen S, Lukas C, Kitagawa R, Melander F, Kastan MB, Bartek J, Lukas J. Spatial organization of the mammalian genome surveillance machinery in response to DNA strand breaks. J Cell Biol. 2006;173(2):195–206. - PMC - PubMed
    1. Berkovich E, Monnat RJ, Jr, Kastan MB. Roles of ATM and NBS1 in chromatin structure modulation and DNA double-strand break repair. Nat Cell Biol. 2007;9(6):683–690. - PubMed
    1. Bradshaw PS, Stavropoulos DJ, Meyn MS. Human telomeric protein TRF2 associates with genomic double-strand breaks as an early response to DNA damage. Nat Genet. 2005;37(2):193–197. - PubMed
    1. Brzovic PS, Meza JE, King MC, Klevit RE. BRCA1 RING domain cancer-predisposing mutations. Structural consequences and effects on protein–protein interactions. J Biol Chem. 2001a;276(44):41399–41406. - PubMed

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