Histone demethylase KDM5A regulates the ZMYND8–NuRD chromatin remodeler to promote DNA repair

Gong, Fade; Clouaire, Thomas; Aguirrebengoa, Marion; Legube, Gaëlle; Miller, Kyle M.

doi:10.1083/jcb.201611135

Cited by 149 publications

(194 citation statements)

References 77 publications

(166 reference statements)

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“…We also recently demonstrated that H3K4me3 decreases at AsiSI-induced DSBs (Gong et al., 2017). Notably, all these modifications were already found to be coordinated and linked to H2B ubiquitination during transcriptional regulation.…”

Section: Discussionmentioning

confidence: 71%

Comprehensive Mapping of Histone Modifications at DNA Double-Strand Breaks Deciphers Repair Pathway Chromatin Signatures

et al. 2018

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SummaryDouble-strand breaks (DSBs) are extremely detrimental DNA lesions that can lead to cancer-driving mutations and translocations. Non-homologous end joining (NHEJ) and homologous recombination (HR) represent the two main repair pathways operating in the context of chromatin to ensure genome stability. Despite extensive efforts, our knowledge of DSB-induced chromatin still remains fragmented. Here, we describe the distribution of 20 chromatin features at multiple DSBs spread throughout the human genome using ChIP-seq. We provide the most comprehensive picture of the chromatin landscape set up at DSBs and identify NHEJ- and HR-specific chromatin events. This study revealed the existence of a DSB-induced monoubiquitination-to-acetylation switch on histone H2B lysine 120, likely mediated by the SAGA complex, as well as higher-order signaling at HR-repaired DSBs whereby histone H1 is evicted while ubiquitin and 53BP1 accumulate over the entire γH2AX domains.

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Section: Discussionmentioning

confidence: 71%

Comprehensive Mapping of Histone Modifications at DNA Double-Strand Breaks Deciphers Repair Pathway Chromatin Signatures

et al. 2018

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“…More interestingly, p53 activation and H2AX phosphorylation were also present in non‐irradiated cells, suggesting that JARID1B depleted cells are more prone to spontaneous DNA breaks . In addition to this, Gong and colleagues also described a similar role for JARID1A: this protein is recruited to the site of damage in a PARP1‐dependent manner and its demethylating activity on pre‐existing H3K4me3 is required for ZMYND8 recruitment to the site of damage, which, in turn, allows NuRD complex association to initiate HR‐related remodeling events . In partial contrast with these observations, Penterling and colleagues suggested that JARID1A's role in DDR is not dependent on its catalytic activity.…”

Section: Introductionmentioning

confidence: 94%

JARID1B expression and its function in DNA damage repair are tightly regulated by miRNAs in breast cancer

et al. 2019

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JARID 1B/ KDM 5B histone demethylase's mRNA is markedly overexpressed in breast cancer tissues and cell lines and the protein has been shown to have a prominent role in cancer cell proliferation and DNA repair. However, the mechanism of its post‐transcriptional regulation in cancer cells remains elusive. We performed a computational analysis of transcriptomic data from a set of 103 breast cancer patients, which, along with JARID 1B upregulation, showed a strong downregulation of 2 microRNAs (mi RNAs ), mir‐381 and mir‐486, potentially targeting its mRNA . We showed that both mi RNA s can target JARID 1B 3′ UTR and reduce luciferase's activity in a complementarity‐driven repression assay. Moreover, MCF 7 breast cancer cells overexpressing JARID 1B showed a strong protein reduction when transfected with mir‐486. This protein's decrease is accompanied by accumulation of DNA damage, enhanced radiosensitivity and increase of BRCA 1 mRNA , 3 features previously correlated with JARID 1B silencing. These results enlighten an important role of a mi RNA’ s circuit in regulating JARID 1B's activity and suggest new perspectives for epigenetic therapies.

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“…In addition, it was recently suggested that WDR5, BRCA1 and BRAD1 were functionally connected to suppress DNA damage during reprogramming (41). ZMYND8 was reported to play roles in activating transcription and promoting HR via multivalent binding to chromatin, including histone H4 acetlylations (30,42,43). In this study, we revealed that USP42, which was previously suggested to enhance transcription by targeting histone H2B ubiquitylation (28), is required for efficient HR.…”

Section: Discussionmentioning

confidence: 57%

A novel nuclear speckle factor, USP42, promotes homologous recombination repair by resolving DNA double-strand break induced R-loop

Matsui

Sakasai

Abe

et al. 2019

Preprint

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The nucleus of mammalian cells is highly compartmentalized by nuclear bodies, including nuclear speckles. While nuclear bodies are known to function in regulating gene expression, their involvement in DNA repair has not been actively investigated. Here, our focused screen for nuclear speckle factors involved in homologous recombination (HR), which is a faithful DNA double-strand break (DSB) repair mechanism, revealed that nuclear speckle factors regulating transcription are potentially involved in the regulation of HR. Among the top hits, we provide evidence showing that USP42, which is a deubiquitylating enzyme and a hitherto unidentified nuclear speckles factor, promotes HR by facilitating BRCA1 recruitment to DSB sites and DNA-end resection. We further showed that USP42 localizes to nuclear speckles via an intrinsically disordered region, which is required for efficient HR. Furthermore, we established that USP42 interacts with DHX9, which possesses DNA-RNA helicase activity, and is required for efficient resolution of DSB-induced R-loop. Mechanistically, USP42antagonizes mono-ubiquitylation of DHX9 that is evoked after DSB induction. In conclusion, our data propose a model in which a novel nuclear speckle factor, USP42, facilitates DSBinduced R-loop resolution, BRCA1 loading to DSB sites and preferential DSB repair by HR, indicating the importance of spatial regulation of DSB repair choice mediated by nuclear bodies. KeywordsNuclear speckles, DNA double-strand break, homologous recombination, USP42, DHX9, Rloop, ubiquitylation, deubiquitylation Significant statementDefects in the repair of DNA double-strand break (DSB), which is one of the most harmful DNA insults, cause human diseases including cancers. It has been suggested that DSBs generated in the coding region tend to be repaired by homologous recombination (HR) that is error-free DSB repair pathway. To reveal the spatial regulation of HR, in this study, we investigated the potential contribution of nuclear bodies, especially nuclear speckles, to HR, identifying a deubiquitylating enzyme USP42 as a HR promoting factor. We found that USP42 deubiquitylates DHX9, facilitates resolution of DNA-RNA hybrid structure and enhances HR through BRCA1 loading to DSB sites.

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Histone demethylase KDM5A regulates the ZMYND8–NuRD chromatin remodeler to promote DNA repair

Cited by 149 publications

References 77 publications

Comprehensive Mapping of Histone Modifications at DNA Double-Strand Breaks Deciphers Repair Pathway Chromatin Signatures

Comprehensive Mapping of Histone Modifications at DNA Double-Strand Breaks Deciphers Repair Pathway Chromatin Signatures

JARID1B expression and its function in DNA damage repair are tightly regulated by miRNAs in breast cancer

A novel nuclear speckle factor, USP42, promotes homologous recombination repair by resolving DNA double-strand break induced R-loop

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