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Aneuploidy in Human Oocytes and Preimplantation Embryos
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
The loss of cohesion and structural integrity of bivalent chromosomes are age-dependent and is one manifestation of “chromosomal aging” in human oocytes (83–85). However, the molecular mechanism underlying loss of cohesion is currently not known. Studies from rodents suggest that the loading of cohesin complexes may be restricted to fetal development (86–88) and subsequently affected during the extended dictyate arrest (89,90). Intriguingly, SMC1β, a meiosis-specific component of meiotic cohesin complexes is haploinsufficient for maintaining the bivalent configuration in mouse oocytes (91,92). Whether depletion of meiotic cohesin complexes underlies cohesion loss in human oocytes is not clear, since loss of cohesin staining does not appear to preferentially affect the chromosomes that have lost their bivalent structure (93). Since only a proportion of cohesin complexes are thought to mediate sister chromatid cohesion in mitotic cells (94,95), it is possible that the cohesive function of the cohesin complexes, an acetylated form of SMC3, may be affected during the extended dictyate arrest. Common genetic variants in cohesin genes have been linked to trisomy 21 risk in a recent genome-wide association study (96).
Roberts Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Apart from ESCO2-related RBS, mutations in SMC1, SMC3, RAD21, NIPBL, HDAC8, and cohesin-associated PDS5/APRIN causing defective SCC (the process in which sister chromatids are paired during the cell cycle) are implicated in the development of Cornelia de Lange syndrome (CdLS). In contrast to RBS, CdLS is a transcription-based disorder that does not exhibit elevated levels of apoptosis or mitotic failure, and its chromatin-bound cohesin is not only involved in sister chromatid tethering, but also transcription regulation (Figure 47.1) [14].
Genetics of mammalian meiosis
Published in C. Yan Cheng, Spermatogenesis, 2018
In addition to SC proteins, cohesins are essential components of the axial/lateral elements. The cohesin complex is required for sister chromatid cohesion in both mitosis and meiosis. The mammalian mitotic cohesin complex consists of two structural maintenance of chromosome (SMC) proteins (SMC1 and SMC3) and two non-SMC subunits (RAD21 and STAG1 or STAG2). Four meiosis-specific paralogues of mitotic cohesins have been identified in mammals: REC8,5,38 RAD21L,39–41 SMC1B,42 and STAG3.43 REC8 and RAD21L are homologous to RAD21. SMC1B bears sequence similarity with SMC1. STAG3 replaces STAG1/STAG2 in meiotic cohesin complexes. All these meiosis-specific cohesin proteins localize to the axial elements. Strikingly, absence of REC8 leads to synapsis between sister chromatids, suggesting that one of the main functions of REC8 is to limit synapsis to homologous chromosomes.38,44 Genetic and cell biological analyses have shown that these meiosis-specific cohesins regulate the axial element formation, axis length, sister chromatid cohesion, and meiotic recombination.45,46
Emerging strategies to target the dysfunctional cohesin complex in cancer
Published in Expert Opinion on Therapeutic Targets, 2019
Konstantinos Mintzas, Michael Heuser
Apart from its fundamental role during DNA replication and mitosis, cohesin is also involved in chromosomal organization, gene regulation, and DNA damage response (Figure 1). At the lowest level of chromosomal organization, chromatin loops and topologically associated domains (TADs) are formed by cohesin, which brings together distal elements of the same chromosome and extrudes a chromatin loop[17]. At the transcriptional level, cohesin interacts with the CCCTC binding factor (CTCF) to form chromatin loops that can bring together distant regulatory elements, thus promoting or blocking DNA transcription[18]. Cohesin also facilitates the DNA repair mechanisms during double-strand breaks by keeping the two parts of the chromatid in close contact until the machineries of homologous recombination or non-homologous end pair joining repair the break [19–21]. Opposing to its role in sister chromatid cohesion, PDS5 facilitates binding of cohesin to the chromatid during loop formation or gene regulation. PDS5 is required for CTCF’s ability to delimit the boundaries of loops and TADs. PDS5 also interacts with BRCA2, a DNA repair protein, and regulates cohesin binding to regulatory elements[22].
Molecular features, prognosis, and novel treatment options for pediatric acute megakaryoblastic leukemia
Published in Expert Review of Hematology, 2019
Federico De Marchi, Marito Araki, Norio Komatsu
Because only 20%–30% of patients with TAM develop AMegL, researchers investigated if additional molecular alterations other than GATA1 mutation are needed for leukemic transformation. Mutations in (1) cohesin, (2) epigenetic regulators, and (3) signaling proteins have been described after exome and targeted sequencing for 49 cases of DS AMegL (Figure 1) [17]. Cohesin is a molecule that contributes to sister chromatin cohesion, chromosome segregation, DNA repair, and transcriptional regulation [32]. Interestingly, 53% of the 49 DS AMegL had mutations in the components of this complex in a mutually exclusive manner, whereas no mutations in cohesin complex were detected in TAM cases. This observation is consistent with the hypothesis that cohesion and mutant GATA1 have a role in evolution from TAM to overt leukemia [33]. Additionally, components of epigenetic regulators such as polycomb repressive complex 2 (PRC2), were found to be mutated in 35% of cases in a mutually exclusive manner but in concomitance with cohesin mutations. PCR2 is involved in silencing of GATA1 repressed genes; therefore, it may contribute to the differentiation block via mutant GATA1 [34]. Lastly, 50% of the 49 cases had mutations in genes involved in megakaryopoiesis and the Ras and signal transducer and activator of transcription (STAT) pathways, including JAK, MPL, KRAS, NRAS, and SH2B3. These mutations activate cytokine-independent growth and can result in megakaryocyte expansion [35].
The crosstalk between DNA damage response components and DNA-sensing innate immune signaling pathways
Published in International Reviews of Immunology, 2022
Feng Lin, Yan-Dong Tang, Chunfu Zheng
STAG2 (stromal antigen 2) is an important component of the cohesin complex involving in genomic stabilization. STAG2 deficiency results in spontaneous genomic DNA damage and robust IFN-I production via the cGAS-STING cytosolic DNA-sensing pathway [45]. Cohesin is a multi-subunit nuclear protein complex that coordinates sister chromatid separation during cell division. Given the association between cohesin and DNA damage, it is tempting to speculate that other proteins in this complex are likely also critical for modulating IFN-I responses and preventing autoimmune or antiviral immunity.