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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.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC3710545 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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ZNF365 promotes stability of fragile sites and telomeres.

Zhang Yuqing Y Shin Sandra J SJ Liu Debra D Ivanova Elena E Foerster Friedrich F Ying Haoqiang H Zheng Hongwu H Xiao Yonghong Y Chen Zhengming Z Protopopov Alexei A Depinho Ronald A RA Paik Ji-Hye JH

Cancer discovery 20130617 7

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 ...[more]

PMID: 23776040

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Project description:Common fragile sites (CFSs) are particularly vulnerable regions of the genome that become visible as breaks, gaps, or constrictions on metaphase chromosomes when cells are under replicative stress. Impairment in DNA replication, late replication timing, enrichment of A/T nucleotides that tend to form secondary structures, the paucity of active or inducible replication origins, the generation of R-loops, and the collision between replication and transcription machineries on particularly long genes are some of the reported characteristics of CFSs that may contribute to their tissue-specific fragility. Here, we validated the induction of two CFSs previously found in the human fetal lung fibroblast line, Medical Research Council cell strain 5 (MRC-5), in another cell line derived from the same fetal tissue, Institute for Medical Research-90 cells (IMR-90). After induction of CFSs through aphidicolin, we confirmed the expression of the CFS 1p31.1 on chromosome 1 and CFS 3q13.3 on chromosome 3 in both fetal lines. Interestingly, these sites were found to not be fragile in lymphocytes, suggesting a role for epigenetic or transcriptional programs for this tissue specificity. Both these sites contained late-replicating genes NEGR1 (neuronal growth regulator 1) at 1p31.1 and LSAMP (limbic system-associated membrane protein) at 3q13.3, which are much longer, 0.880 and 1.4 Mb, respectively, than the average gene length. Given the established connection between long genes and CFS, we compiled information from the literature on all previously identified CFSs expressed in fibroblasts and lymphocytes in response to aphidicolin, including the size of the genes contained in each fragile region. Our comprehensive analysis confirmed that the genes found within CFSs are longer than the average human gene; interestingly, the two longest genes in the human genome are found within CFSs: Contactin Associated Protein 2 gene (CNTNAP2) in a lymphocytes' CFS, and Duchenne muscular dystrophy gene (DMD) in a CFS expressed in both lymphocytes and fibroblasts. This indicates that the presence of very long genes is a unifying feature of all CFSs. We also obtained replication profiles of the 1p31.1 and 3q13.3 sites under both perturbed and unperturbed conditions using a combination of fluorescent in situ hybridization (FISH) and immunofluorescence against bromodeoxyuridine (BrdU) on interphase nuclei. Our analysis of the replication dynamics of these CFSs showed that, compared to lymphocytes where these regions are non-fragile, fibroblasts display incomplete replication of the fragile alleles, even in the absence of exogenous replication stress. Our data point to the existence of intrinsic features, in addition to the presence of long genes, which affect DNA replication of the CFSs in fibroblasts, thus promoting chromosomal instability in a tissue-specific manner.

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ZNF365 promotes stability of fragile sites and telomeres.

Publications

ZNF365 promotes stability of fragile sites and telomeres.

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