N6-Methyladenosine, DNA Repair, and Genome Stability

Qü, Fei; Tsegay, Pawlos S.; Liu, Yuan

doi:10.3389/fmolb.2021.645823

Cited by 24 publications

(13 citation statements)

References 56 publications

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“…Zhang (2017) [34] suggested that this non-canonical DNA repair pathway works independently on phosphorylation of histone H2AX and is based on the formation of hybrid DNA-RNA loops. It was documented that such DNA-RNA structures appear in the genome as a consequence of DNA damage at transcription sites [35].…”

Section: Introductionmentioning

confidence: 99%

PARP dependent recruitment of RNA methylated at 8-adenosine is linked to base excision repair mechanism

Legartová

Suchánková

Bártová

2021

Preprint

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Methylation of RNAs, especially 6-methyladenosine (m6A)-modified RNAs, plays a specific role in DNA damage response (DDR). Here, we observed that 8-methyladenosine (m8A)-modified RNA is recruited to UVA-microirradiated chromatin, which was reduced by inhibiting both DNA methylation and histone acetylation, especially in later phases of DDR. Most importantly, clinically used PARP inhibitor (PARPi), olaparib, prevents both m8A and m6A RNA accumulation at microirradiated chromatin. Testing the effect of PARPi on the efficiency of BER, NHEJ, and HR repair pathways, we observed that NHEJ repair proteins are down-regulated after PARP inhibition and recruitment of XRCC1, a factor of BER, to DNA lesions was abolished entirely. Conversely, the PARP inhibitor, olaparib, enhanced the genome-wide level of γH2AX that significantly interacted with m8A RNA, similar to DNA. Together, we showed that the recruitment of m6A RNA and m8A RNA to DNA lesions is PARP dependent, similarly as XRCC1 playing a role in the BER mechanism. We found that γH2AX likely stabilizes m8A/m6A RNA-DNA hybrid loops that are formed during PARP-dependent non-canonical m6A/m8A-mediated DNA repair pathway.

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Section: Introductionmentioning

confidence: 99%

PARP dependent recruitment of RNA methylated at 8-adenosine is linked to base excision repair mechanism

Legartová

Suchánková

Bártová

2021

Preprint

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“…Additionally, immunogenic biomarkers, LOH, HRD, TNB, ITH, and aneuploidy were also significantly negatively correlated with m6Ascore. The key role of m6A modification mediated regulators in modulating DNA repair and genome stability has gradually attracted attention (38). Some m6A methyltransferases can modify and regulate the levels of RNAs involved in DNA damage and repair, which in turn affect genomic instability (39).…”

Section: Discussionmentioning

confidence: 99%

m6A Modification Patterns With Distinct Immunity, Metabolism, and Stemness Characteristics in Soft Tissue Sarcoma

et al. 2021

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N6-methyladenosine (m6A) RNA methylation has been shown to have prognostic value in cancer. Nonetheless, its potential role regarding immunity, metabolism, and stemness in soft tissue sarcoma (STS) remains unknown. We comprehensively estimated the m6A modification patterns and corresponding immunity, metabolism, and stemness characteristics based on 568 STS samples and 21 m6A regulators. The m6Ascore was constructed to quantify m6A modification patterns in individuals using machine learning algorithms. Two distinct m6A modification patterns among the STS patients were identified, which exhibited differences in prognosis, immune cell infiltration, metabolic pathways, stemness, somatic mutation, and copy number variation. Thereafter, immunity-, metabolism-, and stemness phenotype-related genes associated with m6A modification were identified. Furthermore, patients with lower m6Ascores had increased antitumor immune responses, survival benefit under immunotherapy, tumor mutation burden, immunogenicity, and response to anti-PD-1/L1 immunotherapy. Immunotherapy sensitivity was validated using the IMvigor210 dataset. STS patients with lower m6Ascore might be more sensitive to docetaxel and gemcitabine. Finally, pan-cancer analysis illustrated the significant correlations of m6Ascore with clinical outcomes, immune cell infiltration, metabolism, and stemness. This study revealed that m6A modification plays an important role in immunity, metabolism, and stemness in STS. Evaluating the m6A modification pattern and development of m6Ascore may help to guide more effective immunotherapy and chemotherapy strategies.

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“…LncRNAs also interact with m6A regulators to affect their function. It has been demonstrated that m6A RNA methylation plays important roles in a variety of biological processes, including cell differentiation, embryonic development, cell cycle regulation, circadian cycle, and stress responses ( 20 , 21 ). Growing evidence from in vivo and in vitro experiments and bioinformatic studies suggest that m6A RNA methylation regulators are closely related to the occurrence, developmental pathogenesis, progression and clinical prognosis of various cancers and cardiovascular diseases ( 22 , 23 ).…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic analysis and laboratory experiments reveal potential critical genes and regulatory mechanisms in sepsis-associated acute kidney injury

Liu¹,

Ao²,

Tan³

et al. 2022

Ann Transl Med

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Background Sepsis-associated acute kidney injury (SA-AKI) is one of the most frequent and serious complications of sepsis. However, the transcriptional regulatory network of the pathophysiological mechanism of the kidney has not been revealed. This study identified new mechanisms in SA-AKI using bioinformatics analyses and laboratory-based experiments. Methods We performed transcriptomic profiling of mouse kidneys after cecal ligation and puncture (CLP) to mimic clinical sepsis. RNA from kidney samples from the CLP and control groups was isolated and analyzed using bulk messenger RNA (mRNA)-seq. Differentially expressed genes (DEGs) between the two groups were identified, and GO, KEGG and GSEA pathway enrichment analyses were performed. The protein-protein interaction (PPI) network of DEGs and hub genes was analyzed. The hub genes were verified using quantitative real-time polymerase chain reaction (qPCR) or Western blotting. The interaction network, targeted microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) of hub genes were predicted, and the critical miRNA-hub gene regulatory axis was verified using qPCR, Western blotting, malondialdehyde (MDA) determination and flow cytometry. Correlation analyses of N6-adenosine methylation (m6A) RNA methylation regulators and hub genes and m6A modification analysis were performed. Results A total of 4,754 DEGs were identified between the two groups using high-throughput sequencing. The pathways in which DEGs were enriched included ferroptosis (the highest enrichment score), apoptosis, and the PI3K-Akt, NF-kappa B and IL-17 signaling pathways. Seven ( Hmox1, Spp1, Socs3, Mapk14, Lcn2, Cxcl1 and Cxcl12 ) of the 15 hub genes were involved in the KEGG pathway. mmu-miR-7212-5p-Hmox1 was a key RNA regulatory axis in ferroptosis. m6A RNA methylation modifications were involved in SA-AKI. The correlation analyses showed the close interactions among the m6A RNA methylation regulators and important hub genes. Conclusions The findings of this study provide new insights into the mechanism regulating the occurrence and progression of SA-AKI. The mmu-miR-7212-5p-Hmox1 axis in ferroptosis and m6A RNA methylation regulators may have potential clinical significance for the future treatment of SA-AKI. The datasets generated for this study can be found in the repository of the GEO database (Series number: GSE186822).

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N6-Methyladenosine, DNA Repair, and Genome Stability

Cited by 24 publications

References 56 publications

PARP dependent recruitment of RNA methylated at 8-adenosine is linked to base excision repair mechanism

PARP dependent recruitment of RNA methylated at 8-adenosine is linked to base excision repair mechanism

m6A Modification Patterns With Distinct Immunity, Metabolism, and Stemness Characteristics in Soft Tissue Sarcoma

Transcriptomic analysis and laboratory experiments reveal potential critical genes and regulatory mechanisms in sepsis-associated acute kidney injury

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