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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: 2015-01-17
    Description: Cancer cells rely on telomerase or the alternative lengthening of telomeres (ALT) pathway to overcome replicative mortality. ALT is mediated by recombination and is prevalent in a subset of human cancers, yet whether it can be exploited therapeutically remains unknown. Loss of the chromatin-remodeling protein ATRX associates with ALT in cancers. Here, we show that ATRX loss compromises cell-cycle regulation of the telomeric noncoding RNA TERRA and leads to persistent association of replication protein A (RPA) with telomeres after DNA replication, creating a recombinogenic nucleoprotein structure. Inhibition of the protein kinase ATR, a critical regulator of recombination recruited by RPA, disrupts ALT and triggers chromosome fragmentation and apoptosis in ALT cells. The cell death induced by ATR inhibitors is highly selective for cancer cells that rely on ALT, suggesting that such inhibitors may be useful for treatment of ALT-positive cancers.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4358324/" 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/PMC4358324/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Flynn, Rachel Litman -- Cox, Kelli E -- Jeitany, Maya -- Wakimoto, Hiroaki -- Bryll, Alysia R -- Ganem, Neil J -- Bersani, Francesca -- Pineda, Jose R -- Suva, Mario L -- Benes, Cyril H -- Haber, Daniel A -- Boussin, Francois D -- Zou, Lee -- 102696/Wellcome Trust/United Kingdom -- 102696HABER/Wellcome Trust/United Kingdom -- GM076388/GM/NIGMS NIH HHS/ -- K99/R00 CA166729/CA/NCI NIH HHS/ -- R00 CA166729/CA/NCI NIH HHS/ -- R01 CA129933/CA/NCI NIH HHS/ -- R01 GM076388/GM/NIGMS NIH HHS/ -- T32 GM008541/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Jan 16;347(6219):273-7. doi: 10.1126/science.1257216.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. Departments of Pharmacology & Experimental Therapeutics, and Medicine, Cancer Center, Boston University School of Medicine, Boston, MA 02118, USA. zou.lee@mgh.harvard.edu rlflynn@bu.edu. ; Departments of Pharmacology & Experimental Therapeutics, and Medicine, Cancer Center, Boston University School of Medicine, Boston, MA 02118, USA. ; Laboratoire de Radiopathologie, UMR 967, Institut de Radiobiologie Cellulaire et Moleculaire, CEA Fontenay-aux-Roses, France. ; Deparment of Surgery and Brain Tumor Center, Massachusetts General Hospital, Boston, MA 02115, USA. ; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. Howard Hughes Medical Institute, Massachusetts General Hospital, Charlestown, MA 02129, USA. ; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA. ; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. ; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA. zou.lee@mgh.harvard.edu rlflynn@bu.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25593184" target="_blank"〉PubMed〈/a〉
    Keywords: Antineoplastic Agents/*pharmacology ; Apoptosis ; Ataxia Telangiectasia Mutated Proteins/antagonists & inhibitors/metabolism ; Cell Cycle ; Cell Line, Tumor ; DNA Helicases/genetics/metabolism ; Gene Knockdown Techniques ; Glioma/drug therapy/genetics ; HeLa Cells ; Homologous Recombination ; Humans ; Nuclear Proteins/genetics/metabolism ; Osteosarcoma/drug therapy/genetics ; Pyrazines/*pharmacology ; RNA, Untranslated/genetics/metabolism ; Replication Protein A/metabolism ; Sulfones/*pharmacology ; Telomerase/metabolism ; Telomere/*drug effects/genetics/*metabolism ; *Telomere Homeostasis ; Telomeric Repeat Binding Protein 2/metabolism ; Transcription Factors/metabolism ; Tumor Suppressor Proteins/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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