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  • 1
    Publication Date: 2012-01-20
    Description: The involvement of whole-chromosome aneuploidy in tumorigenesis is the subject of debate, in large part because of the lack of insight into underlying mechanisms. Here we identify a mechanism by which errors in mitotic chromosome segregation generate DNA breaks via the formation of structures called micronuclei. Whole-chromosome-containing micronuclei form when mitotic errors produce lagging chromosomes. We tracked the fate of newly generated micronuclei and found that they undergo defective and asynchronous DNA replication, resulting in DNA damage and often extensive fragmentation of the chromosome in the micronucleus. Micronuclei can persist in cells over several generations but the chromosome in the micronucleus can also be distributed to daughter nuclei. Thus, chromosome segregation errors potentially lead to mutations and chromosome rearrangements that can integrate into the genome. Pulverization of chromosomes in micronuclei may also be one explanation for 'chromothripsis' in cancer and developmental disorders, where isolated chromosomes or chromosome arms undergo massive local DNA breakage and rearrangement.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3271137/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3271137/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Crasta, Karen -- Ganem, Neil J -- Dagher, Regina -- Lantermann, Alexandra B -- Ivanova, Elena V -- Pan, Yunfeng -- Nezi, Luigi -- Protopopov, Alexei -- Chowdhury, Dipanjan -- Pellman, David -- 1R01CA142698-01/CA/NCI NIH HHS/ -- GM083299/GM/NIGMS NIH HHS/ -- R00 CA154531/CA/NCI NIH HHS/ -- R01 CA142698/CA/NCI NIH HHS/ -- R01 GM083299/GM/NIGMS NIH HHS/ -- R01 GM083299-14/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Jan 18;482(7383):53-8. doi: 10.1038/nature10802.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pediatric Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22258507" target="_blank"〉PubMed〈/a〉
    Keywords: *Aneuploidy ; Cell Line, Tumor ; Cell Transformation, Neoplastic/genetics/pathology ; *Chromosome Breakage ; Chromosome Segregation ; Comet Assay ; DNA Fragmentation ; DNA Replication ; Humans ; *Micronuclei, Chromosome-Defective ; *Mitosis/genetics ; Neoplasms/etiology/genetics/pathology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2018-11-02
    Description: The most commonly utilized class of chemotherapeutic agents administered as a first-line therapy are antimitotic drugs; however, their clinical success is often impeded by chemoresistance and disease relapse. Hence, a better understanding of the cellular pathways underlying escape from cell death is critical. Mitotic slippage describes the cellular process where cells exit antimitotic drug-enforced mitotic arrest and "slip" into interphase without proper chromosome segregation and cytokinesis. The current report explores the cell fate consequence following mitotic slippage and assesses a major outcome following treatment with many chemotherapies, therapy-induced senescence. It was found that cells postslippage entered senescence and could impart the senescence-associated secretory phenotype (SASP). SASP factor production elicited paracrine protumorigenic effects, such as migration, invasion, and vascularization. Both senescence and SASP factor development were found to be dependent on autophagy. Autophagy induction during mitotic slippage involved the autophagy activator AMPK and endoplasmic reticulum stress response protein PERK. Pharmacologic inhibition of autophagy or silencing of autophagy-related ATG5 led to a bypass of G 1 arrest senescence, reduced SASP-associated paracrine tumorigenic effects, and increased DNA damage after S-phase entry with a concomitant increase in apoptosis. Consistent with this, the autophagy inhibitor chloroquine and microtubule-stabilizing drug paclitaxel synergistically inhibited tumor growth in mice. Sensitivity to this combinatorial treatment was dependent on p53 status, an important factor to consider before treatment. Implications: Clinical regimens targeting senescence and SASP could provide a potential effective combinatorial strategy with antimitotic drugs. Mol Cancer Res; 16(11); 1625–40. ©2018 AACR .
    Print ISSN: 1541-7786
    Electronic ISSN: 1557-3125
    Topics: Medicine
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