The Functions of Breast Cancer Susceptibility Gene 1 (BRCA1) Product and Its Associated Proteins

Abstract

About half of the familial breast cancer cases are found to bear mutations in the breast cancer susceptibility gene 1 (BRCA1). The majority of BRCA1 mutations produce a truncated protein and BRCA1-associated breast tumors exhibit a number of defined tumor phenotypes. The function of BRCA1 has been examined in gene knockout mice in which the nullizygous mice die early in utero, but this lethality can be partially rescued by a nullizygous p53 mutation. Wild-type BRCA1 protein binds to a number of cellular proteins, including DNA repair protein Rad51, tumor suppressor p53, RNA polymerase II holoenzyme, RNA helicase A, CtBP-interacting protein, c-myc, BRCA1-associated RING domain protein (BARD1), BRCA2 protein, etc. These proteins likely mediate the involvement of BRCA1 in DNA repair, transcriptional transactivation, and cell cycle control. Overall, BRCA1 protein may act as a converging vehicle for cell regulatory proteins to associate with. Therefore, mutations in BRCA1 may affect the composition of these complexes on which dysregulation of cellular functions with eventual development of malignancy is expected.

The Breast Cancer Susceptibility Gene BRCA1 Is Required for Subnuclear Assembly of Rad51 and Survival following Treatment with the DNA Cross-linking Agent Cisplatin

“…BRCA1 and BRCA2 appear to have multiple functions including roles in transcriptional regulation (11)(12)(13)(14) and cell cycle checkpoint control (15)(16)(17)(18)(19)(20).1 Brca1 and Brca2 both have transcription activation functions (11, 13); Brca1 co-activates transcription with p53 (21,22). Recently it has been demonstrated that Brca1 participates in homologous recombinational repair pathways (2, 3).…”

“…BRCA1 and BRCA2 appear to have multiple functions including roles in transcriptional regulation (11)(12)(13)(14) and cell cycle checkpoint control (15)(16)(17)(18)(19)(20).…”

DNA polymerase stalling, sister chromatid recombination and the BRCA genes

“…BRCA1 interacts and colocalizes with the recombination proteins Rad51 (Scully et al, 1997b) and Rad50/ MRE11/NBS1 (Wu et al, 2000;Zhong et al, 1999). Interactions between BRCA1 and several transcription factors (reviewed in Monteiro, 2000), replication factors and chromatin remodeling protein complexes (Bochar et al, 2000;Pao et al, 2000;Yarden and Brody, 1999) have been reported (reviewed in Irminger-Finger et al, 1999). The wildtype C terminus of BRCA1 encodes transcriptional activation functions that are abolished in clinically relevant mutant forms of the BRCA1 C terminus (Chapman and Verma, 1996;Monteiro et al, 1996).…”

A role for BRCA1 in sporadic breast cancer

“…BRCA1 is postulated to mediate the involvement of these proteins in DNA repair, transcriptional transactivation and cell cycle control by acting as a converging vehicle for protein association (Scully et al, 1997a;Anderson et al, 1998;Yu et al, 1998;IrmingerFinger et al, 1999). By affecting BRCA1 protein tertiary structure, BRCA1 mutations may thus disrupt complex associations precipitating dysregulation of cellular functions and eventual progression to malignancy.…”