Understanding the birth of rupture-prone and irreparable micronuclei

Guo, Xihan; Dai, Xueqin; Wu, Xue; Zhou, Tao; Ni, Juan; Xue, Jinglun; Wang, Xu

doi:10.1007/s00412-020-00741-w

Cited by 32 publications

(18 citation statements)

References 116 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…One of the reasons for delayed DNA replication in MNi could be because of DNA replication stress resulting from lack of the enzymes and cofactors required for DNA synthesis and repair. This may be due to defective nuclear envelope assembly of MNi resulting in a lack of nuclear pore complexes; consequently, MNi fail to properly import key proteins that are necessary for the integrity of the nuclear envelope and the genome [ 54 , 61 , 62 , 63 ]. Disruption of the MN membrane may also either result in leakage of DNA into the cytoplasm and/or provide access for cytoplasmic DNAases to attack the DNA in MNi [ 54 , 62 , 63 ].…”

Section: Shattering Of Chromosomes In Mni and Their Subsequent Hypmentioning

confidence: 99%

“…This may be due to defective nuclear envelope assembly of MNi resulting in a lack of nuclear pore complexes; consequently, MNi fail to properly import key proteins that are necessary for the integrity of the nuclear envelope and the genome [ 54 , 61 , 62 , 63 ]. Disruption of the MN membrane may also either result in leakage of DNA into the cytoplasm and/or provide access for cytoplasmic DNAases to attack the DNA in MNi [ 54 , 62 , 63 ]. There is now a substantial body of evidence that DNA from MNi can be sensed by the innate immune system via cyclic GMP-AMP synthase (cGAS), which generates Cyclic guanosine monophosphate–adenosine monophosphate (cGAMP), which in turn activates Stimulator of Interferon Genes (STING), resulting in increased expression of interferon and activation of pro-inflammatory interferon-stimulated genes [ 64 , 65 , 66 , 67 ].…”

Section: Shattering Of Chromosomes In Mni and Their Subsequent Hypmentioning

confidence: 99%

“…Methods to measure the pulverisation of chromosomes trapped in MNi, defective membranes in disrupted MNi, cGAS positive MNi, and leakage of DNA into the cytoplasm in cells containing MNi have been recently published [ 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 ].…”

Section: Shattering Of Chromosomes In Mni and Their Subsequent Hypmentioning

confidence: 99%

See 2 more Smart Citations

Cytokinesis-Block Micronucleus Cytome Assay Evolution into a More Comprehensive Method to Measure Chromosomal Instability

Fenech

2020

Genes

View full text Add to dashboard Cite

This review describes the cytokinesis-block micronucleus (CBMN) cytome assay and its evolution into a molecular cytogenetic method of chromosomal instability (CIN). Micronuclei (MNi) originate from whole chromosomes or chromosome fragments that fail to segregate to the poles of the cell during mitosis. These lagging chromosomes are excluded from the daughter nuclei and are enveloped in their own membrane to form MNi. The CBMN assay was developed to allow MNi to be scored exclusively in once-divided binucleated cells, which enables accurate measurement of chromosome breakage or loss without confounding by non-dividing cells that cannot express MNi. The CBMN assay can be applied to cell lines in vitro and cells such as lymphocytes that can be stimulated to divide ex vivo. In the CBMN assay, other CIN biomarkers such as nucleoplasmic bridges (NPBs) and nuclear buds (NBUDs) are also measured. Use of centromere, telomere, and chromosome painting probes provides further insights into the mechanisms through which MNi, NPBs and NBUDs originate. Measurement of MNi is also important because entrapment within a micronucleus may cause chromosomes to shatter and, after nuclear reintegration, become rearranged. Additionally, leakage of DNA from MNi can stimulate inflammation via the cyclic GMP-AMP Synthase—Stimulator of Interferon Genes (cGAS-STING) DNA sensing mechanism of the innate immune system.

show abstract

Section: Shattering Of Chromosomes In Mni and Their Subsequent Hypmentioning

confidence: 99%

Section: Shattering Of Chromosomes In Mni and Their Subsequent Hypmentioning

confidence: 99%

Section: Shattering Of Chromosomes In Mni and Their Subsequent Hypmentioning

confidence: 99%

See 1 more Smart Citation

Cytokinesis-Block Micronucleus Cytome Assay Evolution into a More Comprehensive Method to Measure Chromosomal Instability

Fenech

2020

Genes

View full text Add to dashboard Cite

show abstract

“…mNE also manifests heterogeneity in the presence or absence of lamin‐A/C 40 . The birth of mNE‐deficient micronuclei may be the cumulative effects of their intracellular geographic origins, biophysical properties and specific mNE features (See Reference 41 for more details). In addition, chromatins in micronuclei can either be highly compacted, normal or decondensed, 42 probably depends on the integrity of mNE.…”

Section: Not All Micronuclei Are Equal: Heterogeneities In the Sourcementioning

confidence: 99%

“…The reason for this heterogeneity may be that mNE‐deficient micronuclei fail to recruit or retain sufficient replication, transcription and DDR factors. The variations in the sources, structures and functions of micronuclei have important consequences for different fates of micronucleated cells 5,41 . For example, comparing to HeLa cells with kinetochore‐negative micronuclei, cells with kinetochore‐positive micronuclei have prolonged mitosis and increased apoptosis 47 …”

Section: Not All Micronuclei Are Equal: Heterogeneities In the Sourcementioning

confidence: 99%

Small but strong: Mutational and functional landscapes of micronuclei in cancer genomes

Guo

Dai

et al. 2020

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

Micronuclei, small spatially-separated, nucleus-like structures, are a common feature of human cancer cells. There are considerable heterogeneities in the sources, structures and genetic activities of micronuclei. Accumulating evidence suggests that micronuclei and main nuclei represent separate entities with respect to DNA replication, DNA damage sensing and repairing capacity because micronuclei are not monitored by the same checkpoints nor covered by the same nuclear envelope as the main nuclei. Thus, micronuclei are spatially restricted "mutation factories." Several large-scale DNA sequencing and bioinformatics studies over the last few years have revealed that most micronuclei display a mutational signature of chromothripsis immediately after their generation and the underlying molecular mechanisms have been dissected extensively. Clonal expansion of the micronucleated cells is contextdependent and is associated with chromothripsis and several other mutational signatures including extrachromosomal circular DNA, kataegis and chromoanasynthesis. These results suggest what was once thought to be merely a passive indicator of chromosomal instability is now being recognized as a strong mutator phenotype that may drive intratumoral genetic heterogeneity. Herein, we revisit the actionable determinants that contribute to the bursts of mutagenesis in micronuclei and present the growing number of evidence which suggests that micronuclei have distinct shortand long-term mutational and functional effects to cancer genomes. We also pose challenges for studying the long-term effects of micronucleation in the upcoming years.

show abstract

Arabidopsis AN3 and OLIGOCELLULA genes link telomere maintenance mechanisms with cell division and expansion control

Agabekian,

Abdulkina,

Lushnenko

et al. 2024

Plant Mol Biol

View full text Add to dashboard Cite

Telomeres are conserved chromosomal structures necessary for continued cell division and proliferation.In addition to the classical telomerase pathway, multiple other genes including those involved in ribosome metabolism and chromatin modi cation contribute to telomere length maintenance. We previously reported that Arabidopsis thaliana ribosome biogenesis genes OLI2/NOP2A, OLI5/RPL5A and OLI7/RPL5B have critical roles in telomere length regulation. These three OLIGOCELLULA genes were also shown to function in cell proliferation and expansion control and to genetically interact with the transcriptional co-activator ANGUSTIFOLIA3 (AN3). Here we show that AN3-de cient plants progressively lose telomeric DNA in early homozygous mutant generations, but ultimately establish a new shorter telomere length setpoint by the fth mutant generation with a telomere length similar to oli2/nop2ade cient plants. Analysis of double an3 oli2 mutants indicates that the two genes are epistatic for telomere length control. Telomere shortening in an3 and oli mutants is not caused by telomerase inhibition; wild type levels of telomerase activity are detected in all analyzed mutants in vitro. Late generations of an3 and oli mutants are prone to stem cell damage in the root apical meristem, implying that genes regulating telomere length may have conserved functional roles in stem cell maintenance mechanisms. Multiple instances of anaphase fusions in late generations of oli5 and oli7 mutants were observed, highlighting an unexpected effect of ribosome biogenesis factors on chromosome integrity.Overall, our data implicate AN3 transcription coactivator and OLIGOCELLULA proteins in the establishment of telomere length set point in plants and further suggest that multiple regulators with pleiotropic functions can connect telomere biology with cell proliferation and cell expansion pathways.

show abstract

Understanding the birth of rupture-prone and irreparable micronuclei

Cited by 32 publications

References 116 publications

Cytokinesis-Block Micronucleus Cytome Assay Evolution into a More Comprehensive Method to Measure Chromosomal Instability

Cytokinesis-Block Micronucleus Cytome Assay Evolution into a More Comprehensive Method to Measure Chromosomal Instability

Small but strong: Mutational and functional landscapes of micronuclei in cancer genomes

Arabidopsis AN3 and OLIGOCELLULA genes link telomere maintenance mechanisms with cell division and expansion control

Contact Info

Product

Resources

About