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Ovarian, Fallopian Tube, and Primary Peritoneal Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Robert D. Morgan, Andrew R. Clamp, Gordon C. Jayson
The most frequently detected genetic mutations in epithelial ovarian cancer occur in BRCA1 and BRCA2; these are estimated to occur in 10–15% of all high-grade serous cases. BRCA1 and BRCA2 have a number of important cellular functions; however, it is their role in DNA repair, in particular HR repair, that is linked to carcinogenesis.15 HR repair is an error-free DNA repair mechanism able to repair DNA double-strand breaks (DSBs).16 It occurs during the S/G2-phase of the cell cycle, at which stage a sister chromatid, containing a homologous DNA sequence, can act as a template for homology-directed repair. In the absence of BRCA1/2 proteins, the alternative error-prone DNA repair pathway, non-homologous end joining (NHEJ), is relied upon to repair DSBs that have resulted from either exogenous or endogenous genotoxins.17 A greater reliance upon the error-prone NHEJ pathway potentiates the risk of acquiring somatic mutations in oncogenes/tumor suppressor genes, thereby risking tumorigenesis. A deficiency in BRCA1/2 proteins in cells containing a germline mono-allelic/heterozygous BRCA1/2 mutation often occurs through somatic loss of the remaining BRCA1/2 wild-type allele, leading to a bi-allelic/homozygous mutation; in keeping with the concept of BRCA1/2 being tumor suppressor genes.
Bloom Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
SCE is a process employed by sexually reproducing organisms to promote genetic diversity in offspring and maintain genome stability at the same time. During meiosis that generates haploid gametes from a diploid progenitor, one round of DNA replication (which segregates homologous chromosomes inherited from different parents) is followed by two successive nuclear divisions (the second of which separates sister chromatids). Triggered by self-inflicted DNA DSB, recombination takes place between homologous chromosomes, and two sister chromatids rejoin with one another and exchange regions of the parental strands in the duplicated chromosomes. Alterations in the BLM protein hinder its ability to unwind DNA for subsequent DNA replication and repair, leading to an increased frequency of SCE (Figure 64.1) [16].
Genetics
Published in Rachel U Sidwell, Mike A Thomson, Concise Paediatrics, 2020
Rachel U Sidwell, Mike A Thomson
NB: After the S phase of the cell cycle, the DNA has already replicated, so the cell contains two identical copies of each of the 46 chromosomes. The identical copies are joined together at a centromere and are called sister chromatids, making up one chromosome. Because the chromosomes are studied in metaphase of mitosis when they are most condensed, we actually always Look at DNA that has replicated, the sister chromatids joined together and appearing as 46 separate chromosome bodies.
Targeting the DNA damage response in pediatric malignancies
Published in Expert Review of Anticancer Therapy, 2022
Jenna M Gedminas, Theodore W Laetsch
Double stranded DNA breaks can be repaired using nonhomologous end joining repair (NHEJ) or homologous recombination (HR). The repair mechanism used is based on the stability of the end of the DNA breaks [11]. NHEJ directly ligates broken DNA without the need for a homologous template [12]. Because it does not rely on a template, it is able to repair double stranded breaks in any phase of the cell cycle, however, it is also more prone to error than homologous recombination. Homologous recombination is responsible for the reactivation of stalled replication forks and repair of double stranded DNA breaks and inter-strand crosslinks [13]. The repair process occurs in three steps. The broken end of the chromosome if first paired with the homologous region on the sister chromatid. That strand is then invaded to form a Holliday junction, or DNA crossover, which generates a DNA duplex from the two different chromatids [14]. The Holliday junction is then translocated along the DNA and eventually cleaved by endonucleases to again form separate DNA molecules [14]. These two processes are activated by several kinase pathways, ataxia telangiectasia mutated (ATM), ataxia telangiectasia related (ATR), and DNA-PK, which when mutated, result in defective double-strand break repair [15].
Emerging strategies to target the dysfunctional cohesin complex in cancer
Published in Expert Opinion on Therapeutic Targets, 2019
Konstantinos Mintzas, Michael Heuser
Sister chromatid cohesion is a fundamental process of the life cycle; it starts shortly prior to DNA replication and is maintained until anaphase, when the last remaining cohesin complexes are removed[9]. Cohesin complexes are assembled and recruited to DNA prior to DNA replication. At first, cohesin encircles one single chromatid; when the replication fork passes through that part of DNA, a single cohesin complex encircles both sister chromatids, thus providing the necessary cohesion for the following steps (Figure 1)[4]. During S and G2 phases, cohesion established by STAG1-containing complexes is necessary for successful replication of telomeres – complex regions that can stall the replication fork. When cells enter metaphase mainly STAG2-containing complexes coordinate the successful distribution of newly formed chromosomes in daughter cells. Sister chromatids are kept in close contact until the mitotic spindles of the microtubules attach to their centromeres. That way, all chromosomes are bi-oriented and mother and daughter centrioles are colocated[10].
Strategic development of AZD1775, a Wee1 kinase inhibitor, for cancer therapy
Published in Expert Opinion on Investigational Drugs, 2018
Siqing Fu, Yudong Wang, Khandan Keyomarsi, Funda Meric-Bernstein
The G2-M checkpoint starts with the activation of Cdk1 via cyclin A and B messenger RNA (mRNA) transcription and protein synthesis. Newly formed Cdk1/cyclin complexes are inactivated via phosphorylation at Y15 ad T14 by the kinases Wee1 and Myt1, respectively, which requires a phosphorylation at a threonine residue T160 in its activation loop of Cdk1 to free the entrance to the active site [16]. In late G2 phase, the switch-like mitotic entry mediated by Cdk1 is activated via the removal of phosphorylation at T14 and Y15 by a dual-specificity phosphatase Cdc25 [17]. Cdk1 initiates a positive feedback loop by further activating Cdc25 through recruiting protein phosphatase 1 (PP1) and polo-like kinase 1 (PLK1) activity to maintain an active conformation of Cdc25. At the onset of mitotic exit, segregation of the sister chromatids is triggered by Cdk1 inactivation, which is followed by the activation of the cytokinesis network that ultimately leads to two equal daughter cells [16].