Deciphering the BRCA1 Tumor Suppressor Network

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 BRCAtargeted 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.The breast cancer early-onset genes BRCA1 and BRCA2 were discovered by positional cloning approaches in kindreds with a high prevalence of breast and ovarian cancer. The initial lack of clarity presented by the domain structure of the proteins was remedied by a series of discoveries that revealed the proteins biochemically interact in large nuclear foci in response to DNA damage and are required to execute homology-directed DNA repair and cell cycle checkpoints (1). These observations strongly suggested that a common function in genome integrity maintenance is necessary to suppress cancer. Subsequent advances in protein purification and mass spectrometry methodologies have led to the expansion of this concept with the discovery that at least 13 different tumor suppressor proteins interact with BRCA1 and BRCA2. Despite these striking similarities, a linear model of BRCA-dependent DNA repair and tumor suppression is challenged by multiple other observations, namely, only ϳ5% of each protein exists in association with the BRCA1-BRCA2 complex, and breast cancers occurring in individuals with germ-line BRCA1 or BRCA2 mutations typically display different histopathologies and gene expression profiles. Coupled with the realization that chemoresistance mechanisms in BRCA1 and BRCA2 mutant cancers also differ, these features have inspired a network model relating BRCA molecular function in DNA repair to tumor suppression. We highlight recent insights into the BRCA tumor suppressor network and stress the connections between basic molecular knowledge of these proteins and their roles in genome integrity, tumor suppression, and response to therapy.

Resveratrol Ameliorates Cardiac Hypertrophy by Down‐regulation of miR‐155 Through Activation of Breast Cancer Type 1 Susceptibility Protein

“…Breast cancer type 1 susceptibility protein (BRCA1), a well‐known tumor suppressor with multiple interacting partners, is predicted to have diverse biological functions 8, 9, 10. However, the role of BRCA1 in protecting cardiac tissue from DNA damage has not been fully explored to date.…”

RING domain–deficient BRCA1 promotes PARP inhibitor and platinum resistance

“…BRCA1 interacts with partner and localizer of BRCA2 (PALB2) through a coiled-coil region that facilitates the formation of a BRCA1-PALB2-BRCA2-RAD51 complex. The BRCA1 C-terminus domains (BRCT) bind phosphorylated proteins such as CtIP and abraxas (5)(6)(7).…”

MERIT40 cooperates with BRCA2 to resolve DNA interstrand cross-links

“…Less well understood is MERIT40, which is not required for DUB activity in vitro but maintains interaction with the other subunits and is required for their stability in cells and localization to DNA damage foci Shao et al 2009;Wang et al 2009). In contrast to BRCA1 nullizygosity, deficiency in either RAP80 or Abraxas is well tolerated in mice Yin et al 2012;Castillo et al 2014), indicating that the most prominent component of DSB foci formation contributes to only a subset of BRCA1 DNA repair function (Huen et al 2009;Jiang and Greenberg 2015).…”