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Review
. 2015 Jul 17;290(29):17724-17732.
doi: 10.1074/jbc.R115.667931. Epub 2015 Jun 5.

Deciphering the BRCA1 Tumor Suppressor Network

Qinqin Jiang  1 , Roger A Greenberg  2
Affiliations
Review

Deciphering the BRCA1 Tumor Suppressor Network

Qinqin Jiang et al. J Biol Chem. .

Abstract

The BRCA1 tumor suppressor protein is a central constituent of several distinct macromolecular protein complexes that execute homology-directed DNA damage repair and cell cycle checkpoints. Recent years have borne witness to an exciting phase of discovery at the basic molecular level for how this network of DNA repair proteins acts to maintain genome stability and suppress cancer. The clinical dividends of this investment are now being realized with the approval of first-in-class BRCA-targeted therapies for ovarian cancer and identification of molecular events that determine responsiveness to these agents. Further delineation of the basic science underlying BRCA network function holds promise to maximally exploit genome instability for hereditary and sporadic cancer therapy.

Keywords: BRCA1; BRCA2; DNA damage response; DNA repair; breast cancer.

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Figures

FIGURE 1.
FIGURE 1.
Domain structure of BRCA1-BARD1 and key interacting partners in the BRCA network. Key interacting partners and mutations referred to in text are indicated. R1699W and V1736A were found in patients with BRCA1 biallelic mutations. K619A, C645R, and V695L mutations within the BARD1 BRCT repeats fail to interact with poly(ADP-ribose) (PAR). NLS, nuclear localization sequence.
FIGURE 2.
FIGURE 2.
Alternative DNA repair pathways compensate for BRCA deficiency. NHEJ and HR are the primary DSB repair pathways. End resection produces single-stranded DNA overhangs, which are required for HR. Alternative DSB repair pathways, single-strand annealing (SSA), and microhomology-mediated end joining (MMEJ) also necessitate end resection and represent compensatory DNA repair mechanisms when BRCA-dependent HR is impaired. Proteins that execute alternative DNA repair mechanisms represent potential targets to selectively kill BRCA mutant cells. RPA, replication protein A.
FIGURE 3.
FIGURE 3.
Determinants of PARPi response. PARP inhibition creates trapped PARP-DNA complexes that require BRCA HR activity during DNA replication. Resistance mechanisms occur due to events that restore HR in BRCA1 mutant cells. This entails secondary reversion mutations that lead to production of partially functional BRCA1 protein. Alternatively, restoration of HR and resistance can occur due to loss of 53BP1 or several of its interacting partners. RPA, replication protein A.
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References

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