ATM-mediated phosphorylation of the chromatin remodeling enzyme BRG1 modulates DNA double-strand break repair

Sj, Kwon; Jh, Park; Park, EJ; Lee, Sang Ah; Hs, Lee; Kang, SW; Kwon, Jongbum

doi:10.1038/onc.2013.556

Cited by 60 publications

(56 citation statements)

References 54 publications

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“…A direct role for SWI/SNF in the DDR is also supported by a proteomic screen that identified BRG1, BRM, and other SWI/SNF subunits as targets of ATM and ATR phosphorylation in response to IR or UV treatment [50]. Recently, a direct link between ATM and BRG1 phosphorylation was confirmed [51]. At a functional level, RNAi has been performed to demonstrate that the BAF60A subunit (also known as SMARCD1) is important for γH2AX induction and cell-cycle arrest in response to IR [50].…”

Section: Discussionmentioning

confidence: 98%

SWI/SNF complexes are required for full activation of the DNA-damage response

et al. 2015

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SWI/SNF complexes utilize BRG1 (also known as SMARCA4) or BRM (also known as SMARCA2) as alternative catalytic subunits with ATPase activity to remodel chromatin. These chromatin-remodeling complexes are required for mammalian development and are mutated in ~20% of all human primary tumors. Yet our knowledge of their tumor-suppressor mechanism is limited. To investigate the role of SWI/SNF complexes in the DNA-damage response (DDR), we used shRNAs to deplete BRG1 and BRM and then exposed these cells to a panel of 6 genotoxic agents. Compared to controls, the shRNA knockdown cells were hypersensitive to certain genotoxic agents that cause double-strand breaks (DSBs) associated with stalled/collapsed replication forks but not to ionizing radiation-induced DSBs that arise independently of DNA replication. These findings were supported by our analysis of DDR kinases, which demonstrated a more prominent role for SWI/SNF in the activation of the ATR-Chk1 pathway than the ATM-Chk2 pathway. Surprisingly, γH2AX induction was attenuated in shRNA knockdown cells exposed to a topoisomerase II inhibitor (etoposide) but not to other genotoxic agents including IR. However, this finding is compatible with recent studies linking SWI/SNF with TOP2A and TOP2BP1. Depletion of BRG1 and BRM did not result in genomic instability in a tumor-derived cell line but did result in nucleoplasmic bridges in normal human fibroblasts. Taken together, these results suggest that SWI/SNF tumor-suppressor activity involves a role in the DDR to attenuate replicative stress and genomic instability. These results may also help to inform the selection of chemotherapeutics for tumors deficient for SWI/SNF function.

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Section: Discussionmentioning

confidence: 98%

SWI/SNF complexes are required for full activation of the DNA-damage response

et al. 2015

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“…The inhibition of SETD2 ’s phosphorylation by long non-coding RNA HOTAIR has been reported to trigger a reduction of trimethylation on histone H3 thirty-sixth lysine, consequently promoting human liver cancer stem cell malignant growth [41]. SMARCA4 , also known as BRG1 , was shown to modulate DNA double-strand break repair by its phosphorylation [42]. It has been suggested that the enzymatic activity of DNMT1 is possibly modulated by phosphorylation [43], and it has been demonstrated that its phosphorylation by AKT1 kinase increases its stability and abundance [15].…”

Section: Discussionmentioning

confidence: 99%

Emerging role of mutations in epigenetic regulators including MLL2 derived from The Cancer Genome Atlas for cervical cancer

Li¹

2017

BMC Cancer

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BackgroundCervical cancer is the second most common cause of cancer deaths in women worldwide. The aim of this study is to exploit novel pathogenic genes in cervical carcinogenesis.MethodThe somatic mutations from 194 patients with cervical cancer were obtained from the Cancer Genome Atlas (TCGA) publically accessible exome-sequencing database. We investigated mutated gene enrichment in the 12 cancer core pathways and predicted possible post-translational modifications. Additionally, we predicted the impact of mutations by scores quantifying the deleterious effects of the mutations. We also examined the immunogenicity of the mutations based on the mutant peptides’ strong binding with major histocompatibility complex class I molecules (MHC-I). The Kaplan-Meier method was used for the survival analysis.ResultsWe observed that the chromatin modification pathway was significantly mutated across all clinical stages. Among the mutated genes involved in this pathway, we observed that the histone modification regulators were primarily mutated. Interestingly, of the 197 mutations in the 26 epigenetic regulators in this pathway, 25 missense mutations in 13 genes were predicted in or around the phosphorylation sites. Only mutations in the histone methyltransferase MLL2 exhibited poor survival. Compared to other mutations in MLL2 mutant patients, we noticed that the mutational scores prioritized mutations in MLL2, which indicates that it is more likely to have deleterious effects to the human genome. Around half of all of the mutations were found to bind strongly to MHC-I, suggesting that patients are likely to benefit from immunotherapy.ConclusionsOur results highlight the emerging role of mutations in epigenetic regulators, particularly MLL2, in cervical carcinogenesis, which suggests a potential disruption of histone modifications. These data have implications for further investigation of the mechanism of epigenetic dysregulation and for treatment of cervical cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3257-x) contains supplementary material, which is available to authorized users.

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“…For instance, PBAF subunit BAF180 mediates p21 expression in breast tumor cells to suppress tumorigenesis (Xia et al 2008), BRG1 is necessary for efficient RB-mediated cell cycle arrest (Strobeck et al 2000), and BRG1 cooperates with ATM to promote the DNA damage response (Kwon et al 2015). Moreover, mutations in SWI/ SNF subunits and TP53 have a tendency toward mutual exclusivity in multiple cancer types, including breast cancer, suggesting that loss of SWI/SNF function may phenocopy p53 loss to mediate oncogenesis (Kadoch et al 2013).…”

Section: Discussionmentioning

confidence: 99%

Mutant p53 cooperates with the SWI/SNF chromatin remodeling complex to regulate VEGFR2 in breast cancer cells

et al. 2015

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Mutant p53 impacts the expression of numerous genes at the level of transcription to mediate oncogenesis. We identified vascular endothelial growth factor receptor 2 (VEGFR2), the primary functional VEGF receptor that mediates endothelial cell vascularization, as a mutant p53 transcriptional target in multiple breast cancer cell lines. Up-regulation of VEGFR2 mediates the role of mutant p53 in increasing cellular growth in two-dimensional (2D) and three-dimensional (3D) culture conditions. Mutant p53 binds near the VEGFR2 promoter transcriptional start site and plays a role in maintaining an open conformation at that location. Relatedly, mutant p53 interacts with the SWI/SNF complex, which is required for remodeling the VEGFR2 promoter. By both querying individual genes regulated by mutant p53 and performing RNA sequencing, the results indicate that >40% of all mutant p53-regulated gene expression is mediated by SWI/SNF. We surmise that mutant p53 impacts transcription of VEGFR2 as well as myriad other genes by promoter remodeling through interaction with and likely regulation of the SWI/SNF chromatin remodeling complex. Therefore, not only might mutant p53-expressing tumors be susceptible to anti VEGF therapies, impacting SWI/SNF tumor suppressor function in mutant p53 tumors may also have therapeutic potential.

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ATM-mediated phosphorylation of the chromatin remodeling enzyme BRG1 modulates DNA double-strand break repair

Cited by 60 publications

References 54 publications

SWI/SNF complexes are required for full activation of the DNA-damage response

SWI/SNF complexes are required for full activation of the DNA-damage response

Emerging role of mutations in epigenetic regulators including MLL2 derived from The Cancer Genome Atlas for cervical cancer

Mutant p53 cooperates with the SWI/SNF chromatin remodeling complex to regulate VEGFR2 in breast cancer cells

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