China
Africa
Explore chapters and articles related to this topic
Molecular Mediator of Prostate Cancer Progression and Its Implication in Therapy
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Samikshan Dutta, Navatha Shree Sharma, Ridwan Islam, Kaustubh Datta
TCGA database suggested mutations in many DNA repair genes like BRCA1, BRCA2, FANCD2, CKD12 and ATM in primary prostate cancer, although it is to be noted that the frequency of DNA repair mutations in localized prostate cancer is low [108, 178, 179]. Interestingly, mutations in DNA repair enzymes (BRCA2, ATM, BRCA1, FANCA, RAD51B, RAD51C, MLH1, and MSH2) are the major disease-specific mutations in mCRPC [180, 181]. The understanding that a quarter of men with mCRPC have mutations in DNA repair pathway genes such as BRCA genes has led to clinical trials with poly ADP ribose polymerase (PARP) inhibitors. PARPs are required to repair the DNA single-strand breaks through base-excision repair. It has been shown that cancer cells with BRCA gene mutations become significantly more sensitive to PARP inhibitors as a therapeutic approach popularly known as synthetic lethal strategy [180, 181]. It is further noted that mutations of other DNA repair pathway genes can be sensitive to PARP inhibitors. These genes are ATM, BRIP1, BARD1, CDK12, CHEK2, FANCA, NBN, PALB2, and RAD51 [182, 183].
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).
Combining inhibition of immune checkpoints and PARP: rationale and perspectives in cancer treatment
Published in Expert Opinion on Therapeutic Targets, 2022
Martina Catalano, Luigi Francesco Iannone, Federica Cosso, Daniele Generali, Enrico Mini, Giandomenico Roviello
The exchange of DNA strands between a pair of DNA segments of the double helix that have a very similar or identical sequence is defined as homologous recombination. This exchange allows one stretch of DNA double helix to act as a template to restore lost or damaged information to the other stretch. It is particularly challenging to repair DNA damage affecting both strands of the double helix that occur in somatic cells during meiosis [16]. Germline mutations in several other HR genes have been linked to tumor predisposition. The most relevant include tumor suppressors BRCA1 and BRCA2 mutations that have a key role in different stages of HR, mainly associated with familial breast and ovarian cancers [17]. However, around 20–25% of epithelial ovarian cancer patients have pathogenic variants in several genes that mostly encode for proteins involved in DDR pathways [18]. Indeed, next generation sequencing revealed that beyond BRCA1/2, mutations in HR genes, such as PALB2, RAD51, ATM, BRIP1, BARD1, and CHEK2 occurs in up to a fifth of the patients with high-grade serous ovarian cancer [18]. Failure in the HR repair system can compromise the elimination of genome mutations and increasing the risk of oncogenesis after the accumulation of DNA damage events [19].
Polygenic and Network-based studies in risk identification and demystification of cancer
Published in Expert Review of Molecular Diagnostics, 2022
Christopher El Hadi, Georges Ayoub, Yara Bachir, Michèle Haykal, Nadine Jalkh, Hampig Raphael Kourie
A new method was also designed by Jia et al. to identify cancer risk modules and assess disease risks based on the modules in the samples [77]. A co-expression network was first constructed followed by the identification of candidate modules and their associated cancer risk. Based on these cancer risk modules, the disease risks of the original samples were calculated. The discovered module genes could be disease genes that can be targeted for treatment. In addition, some of them were found to be related to genes previously described in LC. For example, MCM7, an important subunit of the MCM complex, could be considered a novel therapeutic target. More, BARD1 has isoforms that may be related to invasion and tumor progression, making it useful as a prognostic marker for non-small cell lung cancer. Finally, these risk modules can be said to be related to cancer pathogenesis both in terms of function and interaction because of their strong correlation with the disease genes they include.
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
The RING domain consists of the RING finger, a highly conserved domain that plays a vital role in the ubiquitination pathway. The RING domain interacts with another RING domain of BRCA1-associated RING domain protein 1 (BARD1). The E3-ubiquitin ligase activity of BRCA1 is controlled by the RING finger motif [11]. This ubiquitin ligase activity significantly increases by the formation of BRCA1/BARD1 heterodimers. BRCA1 and BARD1 knockout mice resulted in embryonic lethality [12,13]. However, Exons 11–13 have most of the clinically relevant mutations and are critical for the tumor suppressor function of BRCA1. This region has a serine cluster domain which is targeted by phosphokinase proteins such as ATM, ATR, CHK1, and CHK2. This region also interacts with RAD50-MRE11-NBS1 complex which is critical in repairing double-strand breaks and various proteins such as RAD50, RAD51, BRCA2, PALB2, MYC and RB that are involved in transcription, DNA repair, and cell cycle regulation [14].