B Cells and Humoral Immunity
Constantin A. Bona, Francisco A. Bonilla in Textbook of Immunology, 2019
Two additional mechanisms may also result in class-switching, although they are not thought to occur with significant frequency, if at all. One hypothesis is identical to the differential splicing of a transcript containing μ and δ. If we imagine that RNA polymerase may continue along the DNA transcribing all of the C region genes, then VDJH joined to any isotype can be generated by differential splicing. Another model for class-switching invokes unequal sister chromatid exchange. During mitosis, sister chromatids may exchange some portions of themselves. If the positions of the joints between chromatids are identical, one has homologous recombination, or equal crossing over. The amount of genetic information in each chromatid remains unchanged. If the breaks occur in different positions in the chromatids, one has non-homologous recombination, or unequal crossing over. This results in deletion of genetic information from one chromatid, and its duplication in the other.
Polar body biopsy and its clinical application
David K. Gardner, Ariel Weissman, Colin M. Howles, Zeev Shoham in Textbook of Assisted Reproductive Techniques, 2017
During the first meiotic division, the diploid chromosome content of an oocyte is reduced to two haploid chromosome sets, which both consist of paired chromatids. One paired chromatid set is extruded as part of the first PB. Sperm entry into an oocyte initiates the second meiotic division, whereby the set of paired chromatids is separated and a single chromatid set becomes part of the second PB. After the first meiotic division, the number of the chromosomes in the oocyte and the first PB should be identical and the same holds true for the number of chromatids following the second meiotic division. Numerical chromosomal abnormalities can be caused by non-disjunction, meaning that a whole chromosome is not directed to the proper compartment (either the oocyte or PB). Another mechanism is premature chromatid segregation into two single, separated chromatids, which has been suggested to occur frequently prior to the first meiotic division (27) and has been confirmed by clinical data (19). Premature chromatid segregation during meiosis I can either lead to a balanced situation, where both chromatids remain in the same compartment, or to an unbalanced situation, where the two chromatids are finally allocated to different compartments. Some of the unbalanced segregations that originate in meiosis I in the oocyte can be corrected in meiosis II during formation of the second PB (28), and can even give rise to a normal child (21).
Increase in Mitochondrial DNA Fragments inside Nuclear DNA during the Lifetime of an Individual as a Mechanism of Aging
Shamim I. Ahmad in Aging: Exploring a Complex Phenomenon, 2017
Another possibility is that mtDNA fragments insertion in the pericentromeric region has detrimental effects by affecting the nearby situated centromere. This DNA region binds the modified histone CEN H3 (Cen PA) which in turn binds to microtubules. Therefore, chromatid separation during mitosis could be also affected, also generating chromosome abnormalities like aneuploidy which can be lethal to cells due to chromosome loss. If cell division is finally impeded, this could also impose functional although restricted limitations, as in the case of telomere shortening, to mitotic tissues. On the other hand, pericentromeric areas also influence chromosome binding to the inside of the nuclear envelope favoring chromosome movement, rearrangements, and local recombination. And MaSat, where the mtDNA insertions have been localized, is also involved in heterochromatin formation and sister chromatid cohesion [51].
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].
Mutant ATRX: uncovering a new therapeutic target for glioma
Published in Expert Opinion on Therapeutic Targets, 2018
Santiago Haase, María Belén Garcia-Fabiani, Stephen Carney, David Altshuler, Felipe J. Núñez, Flor M. Méndez, Fernando Núñez, Pedro R. Lowenstein, Maria G. Castro
The role of ATRX in the resolution of G4 and other non-B DNA secondary structures is essential in preserving genomic stability. Consequently, the accumulation of G4 and other secondary structures in ATRX-mutated cells may be a major contributor to genomic instability. ATRX appears to play a critical role in genomic stability preservation and contributes to chromosome dynamics during mitosis [60]. A study performed in HeLa cells shows that ATRX downregulation by siRNA results in abnormal chromosome congression during mitosis [108]. RNAi knock down of ATRX in mouse ES cells also induces a telomere-dysfunction phenotype and reduces chromobox homolog 5 (CBX5) enrichment at telomeres, suggesting that ATRX participates in telomere chromatin integrity maintenance [109]. In addition, studies in transgenic mice show that ATRX contributes to regulation of pericentric heterochromatin structure [110–112]. This is an essential mechanism that coordinates sister centromere cohesion and appropriate separation of chromatids during mitosis. The loss of this mechanism results in centromere instability and aneuploidy [106,113].
Related Knowledge Centers
- Anaphase
- Centromere
- DNA
- Homologous Chromosome
- Ploidy
- Sexual Reproduction
- Sister Chromatids
- Zygosity
- Meiosis
- Chromosome
- DNA