Aberrant RNA methylation triggers recruitment of an alkylation repair complex
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA663914 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12656454_1.fastq.gz | Fastqsanger.gz | |||
| SRR12656454_2.fastq.gz | Fastqsanger.gz | |||
| SRR12656455_1.fastq.gz | Fastqsanger.gz | |||
| SRR12656455_2.fastq.gz | Fastqsanger.gz | |||
| SRR12656456_1.fastq.gz | Fastqsanger.gz |
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Project description:Central to genotoxic responses is their ability to sense highly specific signals to activate the appropriate repair response. We previously reported that the activation of the ASCC-ALKBH3 repair pathway is exquisitely specific to alkylation damage in human cells. Yet the mechanistic basis for the selectivity of this pathway was not immediately obvious. Here, we demonstrate that RNA but not DNA alkylation is the initiating signal for this process. Aberrantly methylated RNA is sufficient to recruit ASCC, while an RNA dealkylase suppresses ASCC recruitment during chemical alkylation. In turn, recruitment of ASCC during alkylation damage, which is mediated by the E3 ubiquitin ligase RNF113A, suppresses transcription and R-loop formation. We further show that alkylated pre-mRNA is sufficient to activate RNF113A E3 ligase in vitro in a manner dependent on its RNA binding Zn-finger domain. Together, our work identifies an unexpected role for RNA damage in eliciting a specific response to genotoxins.
2021-02-01 | GSE158090 | GEO
Project description:Central to genotoxic responses is their ability to sense highly specific signals to activate the appropriate repair response. We previously reported that the activation of the ASCC-ALKBH3 repair pathway is exquisitely specific to alkylation damage in human cells. Yet the mechanistic basis for the selectivity of this pathway was not immediately obvious. Here, we demonstrate that RNA but not DNA alkylation is the initiating signal for this process. Aberrantly methylated RNA is sufficient to recruit ASCC, while an RNA dealkylase suppresses ASCC recruitment during chemical alkylation. In turn, recruitment of ASCC during alkylation damage, which is mediated by the E3 ubiquitin ligase RNF113A, suppresses transcription and R-loop formation. We further show that alkylated pre-mRNA is sufficient to activate RNF113A E3 ligase in vitro in a manner dependent on its RNA binding Zn-finger domain. Together, our work identifies an unexpected role for RNA damage in eliciting a specific response to genotoxins.
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Project description:The SNF2 family chromatin remodeler HELLS has emerged as an important regulator of cell proliferation, genome stability, and several cancer pathways. Significant upregulation of HELLS has been reported in 33 human cancer types. While HELLS has been implicated in DNA damage response, its function in DNA repair is poorly understood. Here we report a new regulatory link between HELLS and single-strand break (SSB) repair in cellular responses to DNA alkylation damage. We found that loss of HELLS impairs SSB repair, and selectively sensitizes cells to DNA alkylating agents and PARP inhibitors (PARPi). Furthermore, we found that HELLS is co-expressed with PARP1 in cancer cells, and its loss is synthetic lethal with homologous recombination deficiency (HRD). This work unveils new functions of HELLS in modulating SSB repair and responses to clinically relevant DNA alkylation damage, thus offering new insights into the potential therapeutic value of targeting HELLS in cancer.
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Project description:DNA base damage arises frequently in all living cells and is an important contributor to mutations and genome instability. The main repair pathway for base damage is base excision repair (BER). How the formation and repair of base lesions are modulated by DNA-binding proteins is poorly understood. Here we used a high-throughput damage mapping method, N-methylpurine-sequencing (NMP-seq), to characterize alkylation damage distribution and BER at yeast transcription factor (TF) binding sites upon the treatment with alkylating agent methyl methanesulfonate (MMS). We found that formation of alkylation damage was mainly suppressed at the binding sites of yeat TFs Abf1 and Reb1, but individual hotspots with elevated damage formation were also observed. Furthermore, our data indicates that repair of alkyhlation damage by BER was significantly inhibited both within the TF core motif and its adajcent DNA. The modulation of damage formation and BER was caused by the TF binding, because lesion formation and repair can be restored by depletion of Abf1 or Reb1 from the nucleus. Finally, we show that repair of UV damage by nucleotide excision repair (NER) was also inhibited at the binding sites of Abf1 and Reb1. A comparision between alkylyation and UV damage repair reveals that NER was inhibited in a broader DNA region relative to BER. Thus, our analyses indicate that TF binding significantly modulates alkylation damage formation and inhibits repair by the BER pathway. The interplay between base damage formation and BER may play an important role in affecting mutation frequency in gene regulatory regions.
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Project description:Chromatin regulator HELLS mediates SSB repair and responses to DNA alkylation damage
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