Abstract:
:Critically short telomeres activate cellular senescence or apoptosis, as mediated by the tumor suppressor p53, but in the absence of this checkpoint response, telomere dysfunction engenders chromosomal aberrations and cancer. Here, analysis of p53-regulated genes activated in the setting of telomere dysfunction identified Zfp365 (ZNF365 in humans) as a direct p53 target that promotes genome stability. Germline polymorphisms in the ZNF365 locus are associated with increased cancer risk, including those associated with telomere dysfunction. On the mechanistic level, ZNF365 suppresses expression of a subset of common fragile sites, including telomeres. In the absence of ZNF365, defective telomeres engage in aberrant recombination of telomere ends, leading to increased telomere sister chromatid exchange and formation of anaphase DNA bridges, including ultra-fine DNA bridges, and ultimately increased cytokinesis failure and aneuploidy. Thus, the p53-ZNF365 axis contributes to genomic stability in the setting of telomere dysfunction.
journal_name
Cancer Discovjournal_title
Cancer discoveryauthors
Zhang Y,Shin SJ,Liu D,Ivanova E,Foerster F,Ying H,Zheng H,Xiao Y,Chen Z,Protopopov A,Depinho RA,Paik JHdoi
10.1158/2159-8290.CD-12-0536subject
Has Abstractpub_date
2013-07-01 00:00:00pages
798-811issue
7eissn
2159-8274issn
2159-8290pii
2159-8290.CD-12-0536journal_volume
3pub_type
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