ZNF365 promotes stability of fragile sites and telomeres.

TitleZNF365 promotes stability of fragile sites and telomeres.
Publication TypeJournal Article
Year of Publication2013
AuthorsZhang Y, Shin SJ, Liu D, Ivanova E, Foerster F, Ying H, Zheng H, Xiao Y, Chen Z, Protopopov A, DePinho RA, Paik J-H
JournalCancer Discov
Date Published2013 Jul
KeywordsCellular Senescence, Chromosome Aberrations, Chromosome Fragile Sites, DNA Damage, DNA-Binding Proteins, Genomic Instability, Humans, Neoplasms, Telomere, Transcription Factors, Tumor Suppressor Protein p53

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.

Alternate JournalCancer Discov
PubMed ID23776040
PubMed Central IDPMC3710545
Grant ListAG-NS-0646-10 / AG / NIA NIH HHS / United States
R01CA84628 / CA / NCI NIH HHS / United States
U01CA141508 / CA / NCI NIH HHS / United States
Related Faculty: 
Hongwu Zheng, Ph.D. Ji-Hye Paik, Ph.D.

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