Biogenesis of micronuclei

Kisurina-Evgenieva, O. P.; Sutiagina, O I; Онищенко, Г. Е.

doi:10.1134/s0006297916050035

Cited by 44 publications

(52 citation statements)

References 83 publications

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“…5A-B; insets). Overall, the structures have characteristics of micronuclei and will hereafter be called micronuclei [46]. The H3S10P antibody preferentially labeled electron-dense material within the core of the structures, indicating the material is hyper-condensed DNA (Fig.…”

Section: Eliminated Dna Is Packaged Into Double Membrane-bound Structmentioning

confidence: 99%

Comprehensive Chromosome End Remodeling During Programmed DNA Elimination

Wang

Veronezi

Zagoskin

et al. 2020

Preprint

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Germline and somatic genomes are typically the same in a multicellular organism. However, in some organisms including the parasitic nematode Ascaris, programmed DNA elimination leads to a reduced somatic genome compared to germline cells. Previous work on the parasitic nematode Ascaris demonstrated that programmed DNA elimination encompasses high fidelity chromosomal breaks at specific genome locations and loss of specific genome sequences including a major tandem repeat of 120 bp and ~1,000 germline-expressed genes. However, the precise chromosomal locations of the 120 bp repeats, the breaks regions, and the eliminated genes remained unknown. Here, we used PacBio longread sequencing and chromosome conformation capture (Hi-C) to obtain fully assembled chromosomes of Ascaris germline and somatic genomes, enabling a complete chromosomal view of DNA elimination.Surprisingly, we found that all 24 germline chromosomes undergo comprehensive chromosome end remodeling with DNA breaks in their subtelomeric regions and loss of distal sequences including the telomeres at both chromosome ends. All new Ascaris somatic chromosome ends are recapped by de novo telomere healing. We provide an ultrastructural analysis of DNA elimination and show that Ascaris eliminated DNA is incorporated into many double membrane-bound structures, similar to micronuclei, during telophase of a DNA elimination mitosis. These micronuclei undergo dynamic changes including loss of active histone marks and localize to the cytoplasm following daughter nuclei formation and cytokinesis where they form autophagosomes. Comparative analysis of nematode chromosomes suggests that germline chromosome fusions occurred forming Ascaris sex chromosomes that become independent chromosomes following DNA elimination breaks in somatic cells. These studies provide the first chromosomal view and define novel features and functions of metazoan programmed DNA elimination.

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Section: Eliminated Dna Is Packaged Into Double Membrane-bound Structmentioning

confidence: 99%

Comprehensive Chromosome End Remodeling During Programmed DNA Elimination

Wang

Veronezi

Zagoskin

et al. 2020

Preprint

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“…If a cell fails to incorporate all chromosomes and chromosome fragments in the reforming nuclei during cell division, micronuclei can be generated (143). Two studies have observed micronuclei associated with LC3 and LAMP2-stained structures (144, 145), and also colocalizing with charged multivesicular body protein 4B (CHMP4B) (145), a member of the ESCRT machinery.…”

Section: Cell Division and Autophagymentioning

confidence: 99%

“…How the autophagy machinery is recruited to micronuclei is, however, not known. Furthermore, as only a small fraction of micronuclei appears to be targeted by autophagy, it remains to be investigated to what extent autophagy contributes to their elimination in comparison to other mechanisms of micronuclei removal, such as extrusion (143). …”

Section: Cell Division and Autophagymentioning

confidence: 99%

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Autophagy and the Cell Cycle: A Complex Landscape

2017

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Autophagy is a self-degradation pathway, in which cytoplasmic material is sequestered in double-membrane vesicles and delivered to the lysosome for degradation. Under basal conditions, autophagy plays a homeostatic function. However, in response to various stresses, the pathway can be further induced to mediate cytoprotection. Defective autophagy has been linked to a number of human pathologies, including neoplastic transformation, even though autophagy can also sustain the growth of tumor cells in certain contexts. In recent years, a considerable correlation has emerged between autophagy induction and stress-related cell-cycle responses, as well as unexpected roles for autophagy factors and selective autophagic degradation in the process of cell division. These advances have obvious implications for our understanding of the intricate relationship between autophagy and cancer. In this review, we will discuss our current knowledge of the reciprocal regulation connecting the autophagy pathway and cell-cycle progression. Furthermore, key findings involving nonautophagic functions for autophagy-related factors in cell-cycle regulation will be addressed.

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“…[67][68][69][70] Micronuclei can also arise during mitosis as a result of mis-repaired double-stranded DNA breaks (DSBs). 71 When a chromosome that has lost its telomere, due to a DSB, is replicated the two ends of the sisters fuse, producing a chromosome with two centromeres (dicentric chromosome). 72,73 During anaphase, the two centromeres are pulled to opposite poles, generating an anaphase bridge.…”

Section: Possible Pathways For the Extrusion Of Cfdnamentioning

confidence: 99%

Sequence analysis of cell-free DNA derived from cultured human bone osteosarcoma (143B) cells

et al. 2018

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The true importance of cell-free DNA in human biology, together with the potential scale of its clinical utility, is tarnished by a lack of understanding of its composition and origin. In investigating the cell-free DNA present in the growth medium of cultured 143B cells, we previously demonstrated that the majority of cell-free DNA is neither a product of apoptosis nor necrosis. In the present study, we investigated the composition and origin of this cell-free DNA population using next-generation sequencing. We found that the cell-free DNA comprises mainly of repetitive DNA, including asatellite DNA, mini satellites, and transposons that are currently active or exhibit the capacity to become reactivated. A significant portion of these cell-free DNA fragments originates from specific chromosomes, especially chromosomes 1 and 9. In healthy adult somatic cells, the centromeric and pericentromeric regions of these chromosomes are normally densely methylated. However, in many cancer types, these regions are preferentially hypomethylated. This can lead to double-stranded DNA breaks or it can directly impair the formation of proper kinetochore structures. This type of chromosomal instability is a precursor to the formation of nuclear anomalies, including lagging chromosomes and anaphase bridges. DNA fragments derived from these structures can recruit their own nuclear envelope and form secondary nuclear structures known as micronuclei, which can localize to the nuclear periphery and bud out from the membrane. We postulate that the majority of cell-free DNA present in the growth medium of cultured 143B cells originates from these micronuclei.

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Biogenesis of micronuclei

Cited by 44 publications

References 83 publications

Comprehensive Chromosome End Remodeling During Programmed DNA Elimination

Comprehensive Chromosome End Remodeling During Programmed DNA Elimination

Autophagy and the Cell Cycle: A Complex Landscape

Sequence analysis of cell-free DNA derived from cultured human bone osteosarcoma (143B) cells

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