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Quantitative Analysis of the Protein Methylome Reveals PARP1 Methylation is involved in DNA Damage Response.

ABSTRACT: Protein methylation plays important roles in DNA damage response. To date, proteome-wide profiling of protein methylation upon DNA damage has been not reported yet. In this study, using HILIC affinity enrichment combined with MS analysis, we conducted a quantitative analysis of the methylated proteins in HEK293T cells in response to IR treatment. In total, 235 distinct methylation sites responding to IR treatment were identified, and 38% of them were previously unknown. Multiple RNA-binding proteins were differentially methylated upon DNA damage stress. Furthermore, we identified 14 novel methylation sites in DNA damage response-related proteins. Moreover, we validated the function of PARP1 K23 methylation in repairing IR-induced DNA lesions. K23 methylation deficiency sensitizes cancer cells to radiation and HU-induced replication stress. In addition, PARP1 K23 methylation participates in the resolution of stalled replication forks by regulating PARP1 binding to damaged forks. Taken together, this study generates a data resource for global protein methylation in response to IR-induced DNA damage and reveals a critical role of PARP1 K23 methylation in DNA repair.

SUBMITTER: Wang X

PROVIDER: S-EPMC9277342 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Quantitative Analysis of the Protein Methylome Reveals PARP1 Methylation is involved in DNA Damage Response.

Wang Xinzhu X Mi Shaojie S Zhao Mingxin M Lu Chen C Jia Chenxi C Chen Yali Y

Frontiers in molecular biosciences 20220629

Protein methylation plays important roles in DNA damage response. To date, proteome-wide profiling of protein methylation upon DNA damage has been not reported yet. In this study, using HILIC affinity enrichment combined with MS analysis, we conducted a quantitative analysis of the methylated proteins in HEK293T cells in response to IR treatment. In total, 235 distinct methylation sites responding to IR treatment were identified, and 38% of them were previously unknown. Multiple RNA-binding prot ...[more]

PMID: 35847980

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Project description:BackgroundSporadic breast cancer like many other cancers is proposed to be a manifestation of abnormal genetic and epigenetic changes. For the past decade our laboratory has identified genes involved in DNA damage response (DDR), apoptosis and immunosurveillance pathways to influence sporadic breast cancer risk in north Indian population. Further to enhance our knowledge at the epigenetic level, we performed DNA methylation study involving 17 gene promoter regions belonging to DNA damage response (DDR) and death receptor apoptotic pathway in 162 paired normal and cancerous breast tissues from 81 sporadic breast cancer patients, using a high throughput quantitative DNA methylation analysis technology.ResultsThe study identified five genes with statistically significant difference between normal and tumor tissues. Hypermethylation of DR5 (P=0.001), DCR1 (P=0.00001), DCR2 (P=0.0000000005) and BRCA2 (P=0.007) and hypomethylation of DR4 (P=0.011) in sporadic breast tumor tissues suggested a weak/aberrant activation of the DDR/apoptotic pathway in breast tumorigenesis. Negative correlation was observed between methylation status and transcript expression levels for TRAIL, DR4, CASP8, ATM, CHEK2, BRCA1 and BRCA2 CpG sites. Categorization of the gene methylation with respect to the clinicopathological parameters showed an increase in aberrant methylation pattern in advanced tumors. These uncharacteristic methylation patterns corresponded with decreased death receptor apoptosis (P=0.047) and DNA damage repair potential (P=0.004) in advanced tumors. The observation of BRCA2 -26 G/A 5'UTR polymorphism concomitant with the presence of methylation in the promoter region was novel and emerged as a strong candidate for susceptibility to sporadic breast tumors.ConclusionOur study indicates that methylation of DDR-apoptotic gene promoters in sporadic breast cancer is not a random phenomenon. Progressive epigenetic alterations in advancing tumors result in aberrant DDR-apoptotic pathway thereby promoting tumor development. We propose, since pathological epigenetic changes of the DDR-apoptotic genes are reversible modifications, these could further be targeted for therapeutic interventions.

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Quantitative Analysis of the Protein Methylome Reveals PARP1 Methylation is involved in DNA Damage Response.

Publications

Quantitative Analysis of the Protein Methylome Reveals PARP1 Methylation is involved in DNA Damage Response.

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