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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