title: ZNF365 promotes stability of fragile sites and telomeres.
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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, USA.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Zhang
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Shin
authors.forename: Debra
authors.initials: D
authors.lastname: Liu
authors.forename: Elena
authors.initials: E
authors.lastname: Ivanova
authors.forename: Friedrich
authors.initials: F
authors.lastname: Foerster
authors.forename: Haoqiang
authors.initials: H
authors.lastname: Ying
authors.forename: Hongwu
authors.initials: H
authors.lastname: Zheng
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Xiao
authors.forename: Zhengming
authors.initials: Z
authors.lastname: Chen
authors.forename: Alexei
authors.initials: A
authors.lastname: Protopopov
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Depinho
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Paik
mesh_terms: D016922:Cellular Senescence / Q000235:genetics; D002869:Chromosome Aberrations; D043283:Chromosome Fragile Sites / Q000235:genetics; D004249:DNA Damage / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D042822:Genomic Instability; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D016615:Telomere / Q000235:genetics* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C475725:ZNF365 protein, human