Multifactorial contributions to an acute DNA damage response by BRCA1/BARD1-containing complexes

Abstract

The BRCA1 gene product and its stoichiometric binding partner, BARD1, play a vital role in the cellular response to DNA damage. However, how they acquire specific biochemical functions after DNA damage is poorly understood. Following exposure to genotoxic stress, DNA damage-specific interactions were observed between BRCA1/BARD1 and the DNA damage-response proteins, TopBP1 and Mre11/Rad50/NBS1. Two distinct DNA damage-dependent super complexes emerged; their activation was dependent, in part, on the actions of specific checkpoint kinases, and each super complex contributed to a distinctive aspect of the DNA damage response. The results support a new, multifactorial model that describes how genotoxic stress enables BRCA1 to execute a diverse set of DNA damage-response functions.[Keywords: BACH1; BARD1; BRCA1; CtIP; M/R/N; TopBP1] Supplemental material is available at http://www.genesdev.org.

Minding the gap: The underground functions of BRCA1 and BRCA2 at stalled replication forks

“…The accumulation of BRCA2, Rad51, BACH1 and CtIP at or near such DSBs is impaired in cells lacking wild-type BRCA1 and is restored by re-expression of wild-type BRCA1 [100]. In contrast, the MRN complex is recruited to DSBs in a BRCA1-independent manner.…”

“…This led to the proposal that BRCA1 and BRCA2 function in daughter strand gap repair [11,28]. Efficient Rad51 focus formation at DSBs induced by laser scissors or ionizing radiation (IR) is dependent upon BRCA1 and BRCA2, and Rad51 retention on chromatin following HU treatment is impaired in the absence of wild-type BRCA2, suggesting a possible role for BRCA1 and 2 in loading Rad51 onto ssDNA [97][98][99][100]. Lomonosov et al visualized replication structures in rDNA of BRCA2 mutant mouse embryonic fibroblasts (MEF) during HU treatment.…”

“…A recent biochemical purification of BARD1 revealed at least three distinct BRCA1/BARD1 complexes: one containing BACH1, the DNA damage responsive protein, TopBP1 and the Mlh1 mismatch repair protein; one containing MRN and CtIP; one containing BRCA2 and Rad51. Each of these complexes contains other polypeptides, and there may be other complexes of BRCA1/BARD1 yet to be described [100]. The interaction of BRCA1/BARD1 with TopBP1 and with MRN is induced following exposure of cells to IR.…”

BRCA1, PARP, and 53BP1: conditional synthetic lethality and synthetic viability

“…BRCA1 interacts with multiple proteins involved in DNA repair and tumorigenesis, including, PALB2, BRIP1/BACH1, CtIP, TOPBP1, Abraxas, and RAP80 and is present in multiple distinct complexes (Wong et al, 1998;Yu et al, 1998;Cantor et al, 2001;Greenberg et al, 2006;Xia et al, 2006;Kim et al, 2007;Sobhian et al, 2007;Wang et al, 2007;Zhang et al, 2009b). Thus, BRCA1 may function partly as a scaffold protein coordinating the assembly of protein complexes involved in mediating HR-mediated DSBR and checkpoint function (Greenberg et al, 2006).…”

“…Thus, BRCA1 may function partly as a scaffold protein coordinating the assembly of protein complexes involved in mediating HR-mediated DSBR and checkpoint function (Greenberg et al, 2006). Mutations that affect the BRCT domains of BRCA1 lead to increased cancer risk in humans, and when homozygous cause embryonic lethality in the mouse (Hohenstein et al, 2001;Williams et al, 2001).…”