Skip to main page content
U.S. flag
See More

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2012 Oct;37(10):418-24.
doi: 10.1016/j.tibs.2012.06.007. Epub 2012 Jul 24.

Links between genome integrity and BRCA1 tumor suppression

Mischa L Li  1 , Roger A Greenberg
Affiliations
Review

Links between genome integrity and BRCA1 tumor suppression

Mischa L Li et al. Trends Biochem Sci. 2012 Oct.

Abstract

BRCA1 and BRCA2 are two major breast and ovarian cancer susceptibility genes. BRCA1 was the first discovered and has been a focus of research for these cancers. BRCA1 mediates tumor suppression in part through pleiotropic interactions with a network of DNA repair proteins on chromatin. BRCA1 mutations cause homologous recombination (HR)-mediated DNA repair deficiency, genomic instability, and DNA-damaging agent hypersensitivity. Although BRCA1 and BRCA2 have some shared functions in cancer predisposition and therapy response, there are also key differences indicating divergent roles for each protein. This review summarizes and highlights recent insights into the molecular events responsible for BRCA1 tumor suppression, emphasizing the DNA repair function of BRCA1 as a nexus between its roles in cancer development and therapy.

PubMed Disclaimer

Figures

Figure 1
Figure 1. The BRCA1 and BRCA2 proteins
Breast cancer type 1 susceptibility protein (BRCA1) and type 2 susceptibility protein (BRCA2) are structurally highly dissimilar. The protein homology domains are shown in blue, commonly mutated residues are indicated above the protein, and a line underneath the protein indicates protein-protein interaction regions. Chk2 and ATM kinases are shown above the protein with arrows to indicate their substrate residues. “Fs” indicates a frameshift mutation. (a) The first 150 N-terminal amino acids of BRCA1 contain the RING domain that associates with BRCA1-associated RING domain protein 1 (BARD1) and has E3 ubiquitin ligase activity. Adjacent to the RING lies a nuclear localization sequence (NLS). The central region of BRCA1 comprises exon 11, which contains phosphorylation substrate residues for ataxia telangiectasia mutated (ATM) (S1387A, S1423A, and S1524A) and checkpoint kinase 2 (Chk2) (S988A) [79]. The coiled-coil domain associates with partner and localizer of BRCA2 (PalB2). The BRCA1 C-terminal BRCT repeats interact with C-terminal binding protein interacting protein (CtIP), coiled-coil domain containing protein 98 (CCDC98/Abraxas) and BTB and CNC homolog 1 (BACH1). I26A is a synthetic mutation that preserves heterodimerization with BARD1 but loses E3 ligase function [80]. All other residues indicated represent common clinical mutations [,,–44]. (b) The N terminus of BRCA2 mediates PalB2 binding. Its central BRC repeats and C-terminal sequences interact with DNA repair protein Rad51 (Rad51). The oligonucleotide-binding domain associates with single-stranded DNA (ssDNA) [79].
Figure 2
Figure 2. BRCA1 protein complexes
During the DNA damage response ataxia telangiectasia mutated (ATM) and checkpoint kinase 2 (Chk2) become activated and phosphorylate many DDR mediators, including BRCA1. Upon ATM and Chk2 phosphorylation, BRCA1 becomes activated and associates with at least four different protein complexes at sites of damage [50], BRCA1-A, BRCA1-B, BRCA1-C, and BRCA1/PalB2/BRCA2 supercomplex. The known functions of these complexes are indicated, and proteins that have clinical mutations in breast and ovarian cancer are marked with an asterisk (*)[–24,28].
Figure 3
Figure 3. Synthetic lethality of PARP inhibition in BRCA1-mutated cancers
Poly(ADP-ribose) polymerase (PARP) inhibition causes persistent single strand DNA breaks that must be repaired by DNA replication-dependent homologous recombination (HR). During DNA replication, these single strand breaks turn into stalled replication forks that must be resolved by double strand break repair mechanisms. In cells expressing at least one wildtype BRCA1 allele, BRCA1 localizes to sites of damage, promoting end resection, enabling these forks to be resolved by BRCA2-Rad51-mediated HR with high fidelity and the cell to continue replication (left side of the figure). In BRCA1-deficient cells (such as in a BRCA1-mutated tumor), 53BP1 occupies sites of damage, preventing adequate end resection and promoting inappropriate NHEJ and radial chromosome formation (right side of the figure)[61,62].
See this image and copyright information in PMC

References

    1. Miki Y, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994;266:66–71. - PubMed
    1. Wooster R, et al. Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995;378:789–792. - PubMed
    1. Futreal PA, et al. BRCA1 mutations in primary breast and ovarian carcinomas. Science. 1994;266:120–122. - PubMed
    1. Moynahan ME, et al. Brca1 controls homology-directed DNA repair. Mol Cell. 1999;4:511–518. - PubMed
    1. Moynahan ME, et al. BRCA2 is required for homology-directed repair of chromosomal breaks. Mol Cell. 2001;7:263–272. - PubMed

Publication types