The Four Causes: The Functional Architecture of Centromeres and Kinetochores

McAinsh, Andrew D.; Marston, Adèle L.

doi:10.1146/annurev-genet-072820-034559

Cited by 39 publications

(30 citation statements)

References 296 publications

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“…Acrocentric segmental duplications promoting interchromosomal duplications between acrocentric and non-acrocentric chromosomes 1, 3, 4, 7, 9, 16, and 20 are particularly prone to double-strand breaks 49 . Large CNVs in pericentromeric regions identified on chromosomes 14, 15, 16, and 19 may modulate the stability of long stretches of constitutive heterochromatin (Table 3 , Supplementary Table S2 ), potentially affecting meiotic chromosome pairing and assembly of the kinetochore complex for chromosomal segregation 50 , 51 . Other reports on SPGF cases have also described CNVs in pericentromeric regions on chromosomes 13–16 52 .…”

Section: Discussionmentioning

confidence: 99%

Microdeletions and microduplications linked to severe congenital disorders in infertile men

Kikas

Punab

Kasak

et al. 2023

Sci Rep

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Data on the clinical validity of DNA copy number variants (CNVs) in spermatogenic failure (SPGF) is limited. This study analyzed the genome-wide CNV profile in 215 men with idiopathic SPGF and 62 normozoospermic fertile men, recruited at the Andrology Clinic, Tartu University Hospital, Estonia. A two-fold higher representation of > 1 Mb CNVs was observed in men with SPGF (13%, n = 28) compared to controls (6.5%, n = 4). Seven patients with SPGF were identified as carriers of microdeletions (1q21.1; 2.4 Mb) or microduplications (3p26.3, 1.1 Mb; 7p22.3-p22.2, 1.56 Mb; 10q11.22, 1.42 Mb, three cases; Xp22.33; 2.3 Mb) linked to severe congenital conditions. Large autosomal CNV carriers had oligozoospermia, reduced or low-normal bitesticular volume (22–28 ml). The 7p22.3-p22.2 microduplication carrier presented mild intellectual disability, neuropsychiatric problems, and short stature. The Xp22.33 duplication at the PAR1/non-PAR boundary, previously linked to uterine agenesis, was detected in a patient with non-obstructive azoospermia. A novel recurrent intragenic deletion in testis-specific LRRC69 was significantly overrepresented in patients with SPGF compared to the general population (3.3% vs. 0.85%; χ2 test, OR = 3.9 [95% CI 1.8–8.4], P = 0.0001). Assessment of clinically valid CNVs in patients with SPGF will improve their management and counselling for general and reproductive health, including risk of miscarriage and congenital disorders in future offspring.

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Section: Discussionmentioning

confidence: 99%

Microdeletions and microduplications linked to severe congenital disorders in infertile men

Kikas

Punab

Kasak

et al. 2023

Sci Rep

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“…The G2 phase detects the completeness of DNA replication, and the cells in which the DNA is under-replicated do not enter mitosis. At the control point of the division spindle assembly, it is checked whether all kinetochores are attached to microtubules [ 43 , 44 , 45 ]. The irreversible damage of DNA activates proapoptotic molecules and induces the programmed cell death.…”

Section: Effect Of D/h Shift On Cell Proliferation and Apoptosismentioning

confidence: 99%

Emerging Role of Deuterium/Protium Disbalance in Cell Cycle and Apoptosis

Yaglova

Timokhina

Обернихин

et al. 2023

IJMS

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Deuterium, a stable isotope of hydrogen, is a component of water and organic compounds. It is the second most abundant element in the human body after sodium. Although the concentration of deuterium in an organism is much lower than that of protium, a wide variety of morphological, biochemical, and physiological changes are known to occur in deuterium-treated cells, including changes in fundamental processes such as cell division or energy metabolism. The mode and degree of changes in cells and tissues, both with an increase and a decrease in the concentration of deuterium, depends primarily on the time of exposure, as well as on the concentration. The reviewed data show that plant and animal cells are sensitive to deuterium content. Any shifts in the D/H balance outside or inside cells promote immediate responses. The review summarizes reported data on the proliferation and apoptosis of normal and neoplastic cells in different modes of deuteration and deuterium depletion in vivo and in vitro. The authors propose their own concept of the effects of changes in deuterium content in the body on cell proliferation and death. The altered rate of proliferation and apoptosis indicate a pivotal role of the hydrogen isotope content in living organisms and suggest the presence of a D/H sensor, which is yet to be detected.

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“…Nucleosomes containing the centromeric histone H3 variant CENP-A mark the region on eukaryotic chromosomes where the kinetochore is assembled, which connects the centromeric DNA to the spindle microtubules [reviewed in ( McAinsh and Marston 2022 )]. Proper assembly of this macromolecular complex is crucial for correct chromosome segregation in mitosis and meiosis, and errors in this process can lead to aneuploidy.…”

Section: Introductionmentioning

confidence: 99%

Methylation of CENP-A/Cse4 on arginine 143 and lysine 131 regulates kinetochore stability in yeast

et al. 2023

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Posttranslational modifications on histones are well known to regulate chromatin structure and function, but much less information is available on modifications of the centromeric histone H3 variant and their effect at the kinetochore. Here, we report two modifications on the centromeric histone H3 variant CENP-A/Cse4 in the yeast Saccharomyces cerevisiae, methylation at arginine 143 (R143me) and lysine 131 (K131me), that affect centromere stability and kinetochore function. Both R143me and K131me lie in the core region of the centromeric nucleosome, near the entry/exit sites of the DNA from the nucleosome. Unexpectedly, mutation of Cse4-R143 (cse4-R143A) exacerbated the kinetochore defect of mutations in components of the NDC80 complex of the outer kinetochore (spc25-1) and the MIND complex (dsn1-7). The analysis of suppressor mutations of the spc25-1 cse4-R143A growth defect highlighted residues in Spc24, Ndc80 and Spc25 that localize to the tetramerization domain of the NDC80 complex and the Spc24-Spc25 stalk, suggesting that the mutations enhance interactions among NDC80 complex components and thus stabilize the complex. Furthermore, the Set2 histone methyltransferase inhibited kinetochore function in spc25-1 cse4-R143A cells, possibly by methylating Cse4-K131. Taken together, our data suggest that Cse4-R143 and -K131 methylation affect the stability of the centromeric nucleosome, which is detrimental in the context of defective NDC80 tetramerization and can be compensated for by strengthening interactions among NDC80 complex components.

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The Four Causes: The Functional Architecture of Centromeres and Kinetochores

Cited by 39 publications

References 296 publications

Microdeletions and microduplications linked to severe congenital disorders in infertile men

Microdeletions and microduplications linked to severe congenital disorders in infertile men

Emerging Role of Deuterium/Protium Disbalance in Cell Cycle and Apoptosis

Methylation of CENP-A/Cse4 on arginine 143 and lysine 131 regulates kinetochore stability in yeast

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