Cancer Res Treat.  2004 Aug;36(4):214-221.

DNA Damage Response Mediated through BRCA1

Affiliations
  • 1Research Institute, National Cancer Center, Goyang, Gyeonggi, Korea. leejs@ncc.re.kr
  • 2College of Natural Sciences, Seoul National University, Seoul, Korea.

Abstract

The BRCA1 gene was identified and cloned in 1994 based on its linkage to early onset breast and ovarian cancer syndromes in women. The tumor suppressor, BRCA1 is known as a major player in the DNA damage response. These are evident from its loss, which causes malignant transformation in breast and ovary, and renders cells to become sensitive to a wide variety of DNA damaging agents. Here, we have implications on functional coupling of the pleiotropic roles of BRCA1, including DNA damage signal networking, DNA repair, transcription, and checkpoint of cell cycle, to tumor suppression by examining the molecular mechanisms and functions of BRCA1. The breast cancer susceptibility 1 (BRCA1) gene was identified and mapped to chromosome 17q21 by analyzing families at high risk from breast and ovarian cancer, and was first cloned in 1994 (1). The BRCA1 gene encodes a large nuclear protein that is ubiquitously expressed in a number of tissues. BRCA1 shares little structural resemblance to the majority of other known proteins (Fig. 1). Its ortholog is only found in mammals but not in yeast, fly, worm, or zebra fish, indicating that BRCA1 may come later in evolution and it may have more specialized and tissue-specific functions in mammalian cells. Although a number of studies delineating and deciphering the real biological roles of BRCA1 have accumulated, understanding these BRCA1 unique features still remains to be challengingly elucidated.


MeSH Terms

Breast
Breast Neoplasms
Cell Cycle
Clone Cells
Diptera
DNA Damage*
DNA Repair
DNA*
Female
Genes, BRCA1
Humans
Mammals
Nuclear Proteins
Ovarian Neoplasms
Ovary
Yeasts
Zebrafish
DNA
Nuclear Proteins

Figure

  • Fig. 1 A schematic diagram of the BRCA1 polypeptide and its interaction with different proteins. BRCA1 polypeptide has the phosphorylation sites (Ⓟ) shown as the seine residues that are phosphorylated and the kinases responsible. The proteins that are interact with BRCA1 are described below the interacting regions in BRCA1. Centrosome proteins, proteins belonging to BASC, and other BRCA2 interacting proteins have been shown to interact with BRCA1 in vivo. The BRCA1 polypeptide has N-terminal RING motif (red), nuclear localization signal (NLS, orange), and two C-terminal BRCT-domains (blue).

  • Fig. 2 Interactions of BRCA1 with a diversity of proteins and its possible roles. The putative cellular functions of protein- protein interactions of BRCA1 are shown in boxes. Their biological significances are not yet clarified.

  • Fig. 3 Hypothetical breast cancer development models based on previously reported genetic and biochemical data. The plausible roadmaps to breast cancers of (A) BRCA1- associated familial and (B) sporadic cases. (A) In familial breast cancer, one additional somatic mutation in the BRCA1 locus (LOH, loss of heterozygosity) in carriers of one germiline mutant BRCA1 allele (BRCA1+/-) results in a complete loss of BRCA1 function (BRCA1-/-). The BRCA1 deficiency (BRCA1-/-), in turn, causes genomic instability. DNA damage triggered by BRCA1 deficiency-induced genomic instability in BRCA1 null (BRCA1-/-) cells can either activate p53-dependent pathways (downward arrow; leading to cell cycle checkpoint, growth arrest, apoptosis, or senescence) or facilitate further mutations of additional breast cancer-associated susceptibility genes (p53, STK11, PTEN, EGFR, Her2 etc), and other tumor suppressor and oncogenes (rightward arrows, leading to carcinogenesis). Genomic instability for survival/growth advantages can be preferred in breast and ovary tissues, while p53 activation for growth arrest/death can be preferred in other tissues. (B) In sporadic breast cancer, the loss or reduction of BRCA1 expression is not necessary for cancer development. Otherwise, carcinogenesis events can be initiated by activation of oncogenes or inactivation of tumor suppressor genes, but not by somatic mutations or silencing BRCA1 (rare but theoretically possible). At least four somatic mutations are required for the development of sporadic breast cancers.

  • Fig. 4 The roles of BRCA1 in DNA damage responses. DNA damage triggers kinases-dependent phosphorylation of BRCA1. BRCA1 can process and integrate DNA damage signal by combination of its phosphorylation sites and extent, and BRCA1 transduces the processed signal to other DNA damage responses (arrow). The diverse functions of BRCA1 and other effectors (cell cycle checkpoint, DNA repair, transcription, and apoptosis), in turn, are regulated and tuned by the processed signal i.e. phosphorylation status of BRCA1. Therefore, BRCA1 might function as not only a signal processor but also a coordinator of various activities in DNA damage responses in order to maintain genome integrity.


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