Domain structure of BRCA1 and BRCA2 The amino acid numbers are listed Biology Diagrams A model illustrating a role of BRCA1 in the C 2 /M cell cycle checkpoint. BRCA1 can be phosphorylated by ATR, ATM and Chk2. BRCA1 regulates expression and cellular localization of Chk1, although it is not clear whether Chk1 can phosphorylates BRCA1. Both Chk1 and Chk2 inactivate Cdc25 by phosphorylate it at Ser-216. The tightly linked cell cycle-dependent expression profile of BRCA1 and BRCA2, with elevated levels at the G1/S transition that remain elevated into G2 and then decline in early G1 (Rajan et al. 1997), and the fact that BRCA1 is hyperphosphorylated in response to DNA damage (Scully et al. 1997c), led to the hypothesis that one or both of CtBP interacting protein (CtIP) is a cell-cycle dependent interactor of BRCA1 and this interaction between both proteins, which occurs at aa 1651-1863 of BRCA1 (Fig. 1), it has been suggested that PALB2 recruitment of BRCA1 is needed to induce the colocalization of BRCA1, BRCA2, PALB2 and RAD51 into the nuclear DNA damage foci,
The greatest risk factor for breast and ovarian cancer is inheritance of a mutation in one of the breast cancer susceptibility genes, BRCA1 or BRCA2.BRCA1 and BRCA2 are tumour suppressor genes, the coding regions of which show no homology to previously described proteins or to each other. If one copy of either gene is mutated in the germ line, the result is hereditary breast and ovarian cancer Since BRCA1 and BRCA2 were cloned five years ago, unraveling their normal functions has posed fascinating problems for cancer biologists. Both genes are novel, and little of their normal function was revealed by their sequence. Both genes contribute to homologous recombination and DNA repair, to embryonic proliferation, to transcriptional regulation and, for BRCA1, to ubiquitination. But
Functional Interactions Between BRCA1 and the Cell Cycle Biology Diagrams
BRCA1 (BReast-CAncer susceptibility gene 1) and BRCA2 are tumor suppressor genes, the mutant phenotypes of which predispose to breast and ovarian cancers. Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage Cancer Sci. 2004 Nov;95(11):866-71. doi: 10.1111/j.1349-7006.2004.tb02195.x The BRCA1 binding protein CtIP has been characterized as a protein that is able to inhibit the transcriptional activation of promoters such as p21WAF1 by BRCA1. 35-37 It is in a complex with BRCA1 and BARD1, but in contrast to BARD1, CtIP is in fact expressed in a cell cycle-dependent manner, roughly mirroring the expression pattern of BRCA1
BRCA1 has also been proposed to be tightly linked to the DNA damage response. Both BRCA1 and another gene product that segregates with breast cancer, BRCA2, are found in complexes with the human RAD51 protein (16, 17).Saccharomyces cerevisiae rad51 mutants are susceptible to DNA-damaging agents. BRCA1 colocalizes with RAD51 and PCNA 1 (16) to nuclear dot structures after the onset of DNA damage.
