Dataset Information

Somatic role of SYCE2: an insulator that dissociates HP1? from H3K9me3 and potentiates DNA repair.

ABSTRACT: The synaptonemal complex is a proteinaceous structure essential for meiotic recombination, and its components have been assumed to play a role exclusively in the germ line. However, SYCE2, a component constituting the synaptonemal complex, is expressed at varying levels in somatic cells. Considering its potent protein-binding activities, it may be possible that SYCE2 plays a somatic role by affecting nuclear functions. Here, we show that SYCE2 constitutively insulates HP1? from trimethylated histone H3 lysine 9 (H3K9me3) to promote DNA double-strand break repair. Unlike other HP1?-binding proteins, which use the canonical PXVXL motifs for their bindings, SYCE2 interacts with the chromoshadow domain of HP1? through its N-terminal hydrophobic sequence. SYCE2 reduces HP1?-H3K9me3 binding without affecting H3K9me3 levels and potentiates ataxia telangiectasia mutated-mediated double-strand break repair activity even in the absence of exogenous DNA damage. Such a somatic role of SYCE2 is ubiquitously observed even if its expression levels are low. These findings suggest that SYCE2 plays a somatic role in the link between the nuclear microenvironment and the DNA damage response potentials as a scaffold of HP1? localization.

SUBMITTER: Hosoya N

PROVIDER: S-EPMC6238414 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Somatic role of SYCE2: an insulator that dissociates HP1α from H3K9me3 and potentiates DNA repair.

Hosoya Noriko N Ono Masato M Miyagawa Kiyoshi K

Life science alliance 20180622 3

The synaptonemal complex is a proteinaceous structure essential for meiotic recombination, and its components have been assumed to play a role exclusively in the germ line. However, SYCE2, a component constituting the synaptonemal complex, is expressed at varying levels in somatic cells. Considering its potent protein-binding activities, it may be possible that SYCE2 plays a somatic role by affecting nuclear functions. Here, we show that SYCE2 constitutively insulates HP1α from trimethylated his ...[more]

PMID: 30456351

Similar Datasets

Project description:Epigenetic alterations occur as organisms age, and lead to chromatin deterioration, loss of transcriptional silencing and genomic instability. Dysregulation of the epigenome has been associated with increased susceptibility to age-related disorders. In this study, we aimed to characterize the age-dependent changes of the epigenome and, in turn, to understand epigenetic processes that drive aging phenotypes. We focused on the aging-associated changes in the repressive histone marks H3K9me3 and H3K27me3 in C. elegans. We observed region-specific gain and loss of both histone marks, but the changes are more evident for H3K9me3. We further found alteration of heterochromatic boundaries in aged somatic tissues. Interestingly, we discovered that the most statistically significant changes reflected H3K9me3-marked regions that are formed during aging, and are absent in developing worms, which we termed "aging-specific repressive regions" (ASRRs). These ASRRs preferentially occur in genic regions that are marked by high levels of H3K9me2 and H3K36me2 in larval stages. Maintenance of high H3K9me2 levels in these regions have been shown to correlate with a longer lifespan. Next, we examined whether the changes in repressive histone marks lead to de-silencing of repetitive DNA elements, as reported for several other organisms. We observed increased expression of active repetitive DNA elements but not global re-activation of silent repeats in old worms, likely due to the distributed nature of repetitive elements in the C. elegans genome. Intriguingly, CELE45, a putative short interspersed nuclear element (SINE), was greatly overexpressed at old age and upon heat stress. SINEs have been suggested to regulate transcription in response to various cellular stresses in mammals. It is likely that CELE45 RNAs also play roles in stress response and aging in C. elegans. Taken together, our study revealed significant and specific age-dependent changes in repressive histone modifications and repetitive elements, providing important insights into aging biology.

Project description:Rationale: Loss of DNA damage repair (DDR) in the tumor is an established hallmark of sensitivity to DNA damaging agents such as chemotherapy. However, there has been scant investigation into gain-of-function alterations of DDR genes in cancer. This study aims to investigate to what extent copy number amplification of DDR genes occurs in cancer, and what are their impacts on tumor genome instability, patient prognosis and therapy outcome. Methods: Retrospective analysis was performed on the clinical, genomics, and pharmacogenomics data from 10,489 tumors, matched peripheral blood samples, and 1,005 cancer cell lines. The key discoveries were verified by an independent patient cohort and experimental validations. Results: This study revealed that 13 of the 80 core DDR genes were significantly amplified and overexpressed across the pan-cancer scale. Tumors harboring DDR gene amplification exhibited decreased global mutation load and mechanism-specific mutation signature scores, suggesting an increased DDR proficiency in the DDR amplified tumors. Clinically, patients with DDR gene amplification showed poor prognosis in multiple cancer types. The most frequent Nibrin (NBN) gene amplification in ovarian cancer tumors was observed in 15 out of 31 independent ovarian cancer patients. NBN overexpression in breast and ovarian cancer cells leads to BRCA1-dependent olaparib resistance by promoting the phosphorylation of ATM-S1981 and homology-dependent recombination efficiency. Finally, integration of the cancer pharmacogenomics database of 37 genome-instability targeting drugs across 505 cancer cell lines revealed significant correlations between DDR gene copy number amplification and DDR drug resistance, suggesting candidate targets for increasing patient treatment response. Principal Conclusions: DDR gene amplification can lead to chemotherapy resistance and poor overall survival by augmenting DDR. These amplified DDR genes may serve as actionable clinical biomarkers for cancer management.

Dataset Information

Somatic role of SYCE2: an insulator that dissociates HP1? from H3K9me3 and potentiates DNA repair.

Publications

Somatic role of SYCE2: an insulator that dissociates HP1α from H3K9me3 and potentiates DNA repair.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets