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Hereditary Breast and Ovarian Cancer
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Functionally, the RING finger motif (residues 24–64) contained within the RING domain (residues 1–109) interacts with BARD1 (BRCA1-associated RING domain protein 1) and dramatically increases the ubiquitin ligase activity of BRCA1, which is fundamental to cell-cycle progression, gene transcription regulation, DNA damage response, and ubiquitination. The two nuclear localization signals (NLS, encoded by exon 11) interact with importin-alpha (involved in BRCA1 transport from the cytosol to the nucleus) and other proteins (e.g., retinoblastoma protein, c-Myc, RAD50, and RAD51) relating to transcription regulation, DNA repair, and cell cycle progression. The C-terminal (BRCT) domain interacts with substrates of DNA damage-activated kinases (e.g., ATM, ATR, Abraxas, CtIP, and BACH1), transcription regulators (e.g., p53 and BACH1), and DNA damage repair proteins (e.g., CtIP and CCDC98). The serine cluster domain (in exons 11–13) contains serine residues (988, 1189, 1387, 1423, 1457, 1524, and 1542) that can be phosphorylated by ATM, ATR, CHK1, or CHK2 [8].
The genetics of breast and ovarian cancer
Published in J. K. Cowell, Molecular Genetics of Cancer, 2003
Phillippa J. Neville, Sarah J. Morland, Susan A. J. Vaziri, Graham Casey
Both BRCA1 and BRCA2 are large genes. BRCA1 encodes a protein of 1863 amino acids, whereas BRCA2 encodes a protein of 3418 amino acids. BRCA1 and BRCA2 share little homology with each other or with other known genes. However, both genes contain recognizable structural motifs (Figure 2). BRCA1 contains an amino terminus RING zinc finger domain and two carboxyl terminus BRCT (BRCA1 carboxyl terminus) repeats (Callebaut and Mornon, 1997; Koonin et al., 1996; Paterson, 1998). The BRCT domain is a poorly conserved domain found in several proteins many of which are involved in DNA repair, such as RAD9 and XRCC1 (Callebaut and Mornon, 1997; Koonin et al., 1996). The protein BARD1 (BRCA1 -associated ring domain) has been shown to associate with the RING finger domain of BRCA1 (Wu et al., 1996). A conserved feature of BRCA2 is the presence of eight copies of a 30–80 amino acid repeat (BRC repeat) (Bignell et al., 1997; Bork et al., 1996).
Development and implementation of precision therapies targeting base-excision DNA repair in BRCA1-associated tumors
Published in Expert Review of Precision Medicine and Drug Development, 2019
Adel Alblihy, Katia A. Mesquita, Maaz T. Sadiq, Srinivasan Madhusudan
Two nuclear localization sequences (NLS) are located in exon 11 which encode almost 60% of the BRCA1 protein. The NLS plays a role in facilitating the interaction of the protein with importin-alpha, which mediates the transport of BRCA1 from the cytosol to the nucleus. NLS mutations lead to a shift towards cytosolic localization of BRCA1, leading to increased unrepaired mutations and chromosomal abnormalities in tumors [15,16]. The BRCT domain is located between amino acids 1650–1863 and facilitates the interaction of BRCA1 with ataxia-telangiectasia mutated (ATM), ataxia telangiectasia and Rad3-related protein (ATR) and multiple transcriptional regulators [17]. BRCT domain mutations destroy the capability of BRCA1 to interact with phosphoproteins. These mutations have been found in breast and ovarian cancers, suggesting that the BRCT domain is involved in tumor suppressor function. The BRCT has also been demonstrated to mediate interactions with proteins phosphorylated by ATM and ATR such as CtlP and BACH1 and to facilitate BRCA1 DNA-binding activity [18].
Association of XRCC1 and XPD functional gene variants with nicotine dependence and/or schizophrenia: a case-control study and in silico analysis
Published in Psychiatry and Clinical Psychopharmacology, 2019
S. Pehlivan, N. Aydin, A. F. Nursal, M. A. Uysal, M. Pehlivan, A. Tekcan, F. K. Yavuz, U. Sever, H. Yavuzlar, S. Kurnaz, S. Uysal, P. C. Aydin
XRCC1 plays a pivotal role in the DNA repair pathway since it could specifically interact with nicked and gapped DNA, promptly and temporarily responds to DNA damage in cells, thereby may act as a strand-break sensor [33]. Furthermore, XRCC1 could interact with many proteins known to take part in BER and SSBs; so it has been suggested that XRCC1 may act as a scaffold protein able to modulate the steps of several DNA repair pathways [34]. Cells that carry a mutant XRCC1 gene have a higher sensitivity to ionizing radiation and alkylating agents [35]. XRCC1 codon 399 is found within the BRCT domain (amino acids 301–402) that collaborates with poly (ADP-ribose) polymerase (PARP) [36]. The Arg399Gln variant in exon 10 of the XRCC1 plays a role in the amino acid substitution (glutamine to arginine). The action of XRCC1 in BER gathers DNA polymerase, DNA ligase III, and PARP at the site of DNA damage; so the rs25487 variant could have an altered repair activity [36]. Also, this variant may be related with some phenotypic changes, such as elevated sister chromatid exchange, glycophorin A mutations, polyphenol DNA adducts, aflatoxin B1–DNA adducts, and prolonged cell cycle delay [37]. Relation of the XRCC1 variants with various cancer types and in various populations has been studied [35].