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BRCA Mutation and PARP Inhibitors
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Arjun Mittra, James H. Doroshow, Alice P. Chen
BRCA1 and 2 are tumor suppressor genes that are located on chromosomes 17 and 13, respectively. Wild-type BRCA genes code for proteins that are integral for HR. The BRCA1 protein migrates to the DNA double strand break (DSB) site to recruit proteins that aid in DNA repair and is involved in cell cycle replication arrest. BRCA2 is directly involved in repairing DNA, at least in part by chaperoning RAD51, a recombination enzyme [127, 128].
Cutaneous Malignant Melanoma
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The BRCA2 (breast cancer type 2 susceptibility protein or BRCA2 DNA repair-associated) gene on chromosome 13q13.1 measures 85 kb in length and encodes a 3418 aa, 384 kDa protein (BRCA2) involved in double-strand break repair and/or homologous recombination. BRCA2 contains several 70 aa motifs (BRC motifs) that mediate binding to the RAD51 recombinase involved in DNA repair through homologous recombination. Germline mutations in BRCA2 predispose to a range of cancer types including melanoma. While BRCA2 pathogenic variants are found in 3% of patients with familial ocular melanoma, they do not seem to be involved in familial CMM.
Pharmacologic Ascorbate Influences Multiple Cellular Pathways Preferentially in Cancer Cells
Published in Qi Chen, Margreet C.M. Vissers, Cancer and Vitamin C, 2020
Qi Chen, Kishore Polireddy, Ping Chen, Ramesh Balusu, Tao Wang, Ruochen Dong
After the DDR signaling pathways activate the DNA repair machinery in the cell, DSBs are repaired by two distinct pathways such as homologous recombination (HR) and nonhomologous end joining (NHEJ). HR is the most used mechanism in which genetic material is exchanged between sister chromatids to repair the damaged DNA without loss of nucleotides. During HR, the enzymes Rad51 and Dmc1 catalyze pairing and shuffling of homologous DNA sequences in mammalian cells, leading to precise repair of the damaged sites. This process is enhanced by breast tumor suppressor BRCA1/2 [20]. During NHEJ, broken ends are brought together and rejoined by DNA ligation, generally with the loss of one or more nucleotides at the site of joining; hence, it is an error-prone DNA repair mechanism. The protein Ku heterodimer (Ku70 and Ku80) recognizes DSBs and acts as a scaffold to recruit the other NHEJ factors, such as DNA-PKcs, x-ray cross complementing protein 4, DNA ligase IV, XRCC4-like factor, and aprataxin-and-PNK-like factor, to DSBs to complete the ligation process [21]. Recent data showed that pharmacologic ascorbate suppresses the expression of HR repair proteins including BRCA1, BRCA2, and RAD51, thus leading to HR deficiency and sensitizing the BRCA1/2 wild-type epithelial ovarian cancer cells to PARP inhibition [22]. Meanwhile, in the presence of HR deficiency, pharmacologic ascorbate also impeded the NHEJ pathway, leading to DNA repair deficiency [22].
Transcriptomic analysis of the Non-Obstructive Azoospermia (NOA) to address gene expression regulation in human testis
Published in Systems Biology in Reproductive Medicine, 2023
Govindkumar Balagannavar, Kavyashree Basavaraju, Akhilesh Kumar Bajpai, Sravanthi Davuluri, Shruthi Kannan, Vasan S. Srini, Darshan S. Chandrashekar, Neelima Chitturi, Kshitish K. Acharya
SP1 has been reported to be one of the key transcriptional regulators for normal spermatogenesis (Thomas et al. 2007; Zhu et al. 2016). It plays a role in chromatin remodeling and DNA damage break repair (Beishline and Kelly 2012). Chromatin remodeling is a key process during the protamine transition process in the post-meiosis stage of spermatogenesis (Govin et al. 2004; Rathke et al. 2014). RAD51 is essential for spermatogonia maintenance and meiotic progression (Qin et al. 2022), mainly for the prophase stage (Dai et al. 2017). Heat shock family proteins are known to play a role in spermatogenesis (Chalmel et al. 2012; Hemati et al. 2020), but HSF4, which is explored in limited cases (Syafruddin et al. 2021), has been known to be an activator as well as a repressor (Tanabe et al. 1999) and required for cell differentiation (Fujimoto et al. 2004). However, its implication in spermatogenesis and NOA condition is highlighted only by the current study.
Poly (ADP-ribose) polymerase (PARP) as target for the treatment of epithelial ovarian cancer: what to know
Published in Expert Opinion on Investigational Drugs, 2021
Luigi Della Corte, Virginia Foreste, Claudia, Di Filippo, Pierluigi Giampaolino, Giuseppe Bifulco
Although both have a direct role in DNA, the roles played by BRCA1 and BRCA2 are quite different: the former acts in signaling DNA damage and in cell-cycle check-point regulation, the latter controls the activity and assembly of the essential recombination enzyme RAD51 involved in DNA repair [30]. BRCA1/BRCA2 mutations and other homologous recombination deficiency (HRD) phenotypes (i.e., proteins such as ATM, RAD51, and ATR) have been identified in multiple different tumor types, including EOC [16]. Additional genomic alterations have been recognized, including Fanconi anemia genes (BRIP1, PALB2), and genes involved in HR pathways either directly (CHEK2, BARD1, NBN) or indirectly (CDK 12). However, their real effect over the assessment of EOC risk is still uncertain [31]. The BRCA1/2 deficiency produces cell dependency from alternative DNA repairs such as non-homologous end joining (NHEJ) and microhomology-mediated end joining (MMEJ) [32]. Among these alternative pathways, PARP1, member of the PARP (Poly ADP-ribose polymerases) superfamily of 17 nucleoproteins, plays critical roles in maintaining genomic integrity supporting single-strand break (SSB) repair, double-strand DNA breaks repair, and damage to replication forks [33].
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
BRCA1 plays a critical role in maintaining genomic integrity by interacting with proteins involved in DNA repair pathways. BRCA1 is involved in homologous recombination (HR) by localizing to RAD51 nuclear foci during the S and G phases of the cell cycle. Furthermore, BRCA1 interacts with the MRN complex (MRE11-RAD50-NBS1) in response to DNA damage and colocalizes with several proteins involved in HR such as ATM, RAD51, RPA at the site of the DNA damage [57]. Furthermore, BRCA1 was reported to function as an MRN complex regulator by inhibiting the nuclease activity of MRE11 [58]. However, the role of BRCA1 in Non-homologous end joining (NHEJ) is somewhat debatable, as BRCA1 has been shown to be suppressed, be a facilitator or with no effect on NHEJ [59]. These contrasting observations may be because BRCA1 plays different roles in different NHEJ subtypes.