Genetics in neonatal surgical practice
Prem Puri in Newborn Surgery, 2017
To successfully package vast amounts of DNA into each cell nucleus, it must be compressed and compacted. The first coiling of DNA is in the form of the double helix. The negatively charged DNA double helix is then bound tightly to and wound 1.65 times around a core of eight positively charged histone proteins to form a nucleosome. The addition of another histone completes the second winding of DNA about the histone core to form a chromatosome. These units stack up and form loops of approximately 300 nm. These are stacked, compressed, and folded into fibers of 250 nm wide. These fibers are then tightly coiled to form a chromatid. Two sister chromatids make up a single chromosome, joined by a centromere. The centromere represents a division along the chromatids in a chromosome, creating a short arm “p” and a long arm “q.”
Ovarian, Fallopian Tube, and Primary Peritoneal Cancer
Pat Price, Karol Sikora in Treatment of Cancer, 2020
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.
Individual conditions grouped according to the international nosology and classification of genetic skeletal disorders*
Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow in Fetal and Perinatal Skeletal Dysplasias, 2012
Genetics: autosomal recessive disorder caused by mutations in the gene ESCO2 (establishment of cohesion 1 homolog 2), encoding an acetyltransferase required for the establishment of sister chromatid cohesion during the S phase of the cell cycle. Cohesion of sister chromatids is essential for correct chromosome segregation and genomic stability. Cells of patients affected by RBS show a phenomenon known as premature centromere separation (PCS) or heterochromatin repulsion (HR), which manifests itself as absence of the centromeric constriction and ‘puffing’ at the heterochromatic regions. This phenomenon can cause random chromosome loss and micronuclei and/or nuclear lobulation in the interphase cells. RBS cells also exhibit hypersensitivity to clastogens such as mitomycin C (MMC), cisplatin and gamma and UV radiation. Because of the cohesion defect, there is an increase in cell death and a decreased proliferation capacity, which is at the root of the reduced growth and developmental phenotype in RBS.
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].
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].
Ameliorative effects of curcumin towards cyclosporine-induced genotoxic potential: an in vitro and in silico study
Published in Drug and Chemical Toxicology, 2018
Ankita J. Shah, Sivakumar Prasanth Kumar, Mandava V. Rao, Himanshu A. Pandya
A total of 100 consecutive metaphase plates per culture were analyzed to score SCEs and differentially stained metaphase plates (first division – M1, second division – M2 and third or successive divisions – M3). Metaphases in their second in vitro division were selected for scoring of SCEs on the basis of the spreading of chromosomes and differentiation of chromatids. In these preparations, cells dividing for the first (M1), second (M2), third or successive (M3) divisions in cultures containing BrdU were designated by the differential staining pattern of sister chromatids. The M1 cells contained chromosomes with both sister chromatids stained uniformly dark. The M2 cells contained only differentially stained chromatids with one chromatid darkly stained and its sister chromatid lightly stained, whereas M3 cells constituted three distinct chromosomal/chromatid features: (a) both sister chromatids stained lightly, (b) chromosomes with a dark and a faint chromatid or (c) chromosomes with a portion that has sister chromatid differentiation and the remaining portion that has both lightly stained chromatids.