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Loss of ATRX,genome instability,and an altered DNA damage response are hallmarks of the alternative lengthening of Telomeres pathway
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نویسنده
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lovejoy c.a. ,li w. ,reisenweber s. ,thongthip s. ,bruno j. ,de lange t. ,de s. ,petrini j.h.j. ,sung p.a. ,jasin m. ,rosenbluh j. ,zwang y. ,weir b.a. ,hatton c. ,ivanova e. ,macconaill l. ,hanna m. ,hahn w.c. ,lue n.f. ,reddel r.r. ,jiao y. ,kinzler k. ,vogelstein b. ,papadopoulos n. ,meeker a.k.
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منبع
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plos genetics - 2012 - دوره : 8 - شماره : 7
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چکیده
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The alternative lengthening of telomeres (alt) pathway is a telomerase-independent pathway for telomere maintenance that is active in a significant subset of human cancers and in vitro immortalized cell lines. alt is thought to involve templated extension of telomeres through homologous recombination,but the genetic or epigenetic changes that unleash alt are not known. recently,mutations in the atrx/daxx chromatin remodeling complex and histone h3.3 were found to correlate with features of alt in pancreatic neuroendocrine cancers,pediatric glioblastomas,and other tumors of the central nervous system,suggesting that these mutations might contribute to the activation of the alt pathway in these cancers. we have taken a comprehensive approach to deciphering alt by applying genomic,molecular biological,and cell biological approaches to a panel of 22 alt cell lines,including cell lines derived in vitro. here we show that loss of atrx protein and mutations in the atrx gene are hallmarks of alt-immortalized cell lines. in addition,alt is associated with extensive genome rearrangements,marked micronucleation,defects in the g2/m checkpoint,and altered double-strand break (dsb) repair. these attributes will facilitate the diagnosis and treatment of alt positive human cancers. © 2012 lovejoy et al.
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آدرس
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laboratory for cell biology and genetics,the rockefeller university,new york,ny, United States, laboratory for cell biology and genetics,the rockefeller university,new york,ny, United States, laboratory for cell biology and genetics,the rockefeller university,new york,ny, United States, laboratory for cell biology and genetics,the rockefeller university,new york,ny, United States, laboratory for cell biology and genetics,the rockefeller university,new york,ny, United States, laboratory for cell biology and genetics,the rockefeller university,new york,ny, United States, molecular biology program,sloan-kettering institute,memorial sloan-kettering cancer center,new york,ny, United States, molecular biology program,sloan-kettering institute,memorial sloan-kettering cancer center,new york,ny, United States, developmental biology program,sloan-kettering institute,memorial sloan-kettering cancer center,new york,ny, United States, developmental biology program,sloan-kettering institute,memorial sloan-kettering cancer center,new york,ny, United States, broad institute of harvard and mit,cambridge,ma, United States, broad institute of harvard and mit,cambridge,ma,united states,department of medical oncology,dana-farber cancer institute,boston,ma, United States, broad institute of harvard and mit,cambridge,ma, United States, department of medical oncology,dana-farber cancer institute,boston,ma, United States, department of medical oncology,dana-farber cancer institute,boston,ma, United States, department of medical oncology,dana-farber cancer institute,boston,ma, United States, department of medical oncology,dana-farber cancer institute,boston,ma, United States, broad institute of harvard and mit,cambridge,ma,united states,department of medical oncology,dana-farber cancer institute,boston,ma, United States, department of microbiology and immunology,w. r. hearst microbiology research center,weill medical college,cornell university,new york,ny, United States, children's medical research institute,westmead,nsw,australia,sydney medical school,university of sydney,sydney,nsw, Australia, ludwig center for cancer genetics and therapeutics,johns hopkins sidney kimmel cancer center,baltimore,md, United States, ludwig center for cancer genetics and therapeutics,johns hopkins sidney kimmel cancer center,baltimore,md, United States, ludwig center for cancer genetics and therapeutics,johns hopkins sidney kimmel cancer center,baltimore,md,united states,howard hughes medical institutions,johns hopkins sidney kimmel cancer center,baltimore,md, United States, ludwig center for cancer genetics and therapeutics,johns hopkins sidney kimmel cancer center,baltimore,md, United States, department of pathology,johns hopkins university school of medicine,baltimore,md, United States
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Authors
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