Chromatin regulator HELLS mediates SSB repair and responses to DNA alkylation damage
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PROVIDER: PRJNA1195851 | ENA |
REPOSITORIES: ENA
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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.
2025-07-01 | GSE283831 | GEO
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.
2021-12-31 | GSE183622 | 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.
2021-02-01 | GSE158090 | GEO
Project description:The activating E2F-transcription factors are best known for their dependence on the Retinoblastoma protein and their role in cellular proliferation. E2F3 is uniquely amplified in specific human tumours where its expression is inversely correlated with the survival of patients. Here, E2F3 interaction partners were identified by mass spectrometric analysis. We show that the SNF2-like HELLS interacts with E2F3 in vivo and cooperates with its oncogenic functions. Depletion of HELLS severely perturbs the induction of E2F-target genes, hinders cell cycle re-entry and growth. Using chromatin immmunoprecipitation coupled to sequencing we identified genome-wide targets of HELLS and E2F3. Our analysis revealed that HELLS binds near promoters of active genes, including the trithorax-related MLL1, and co-regulates E2F3-dependent genes. Our analysis is the first to link HELLS with E2F-controlled processes that are critical to establish a proliferative tumour circuitry. Strikingly, just as E2F3, HELLS is overexpressed in human tumours including prostate cancer, indicating that either factor may contribute to the malignant progression of tumours. Our work reveals that HELLS is important for E2F3 in tumour cell proliferation. Examination of E2F3, Hells, and H3K27me3 in 2 cell types.
2011-12-19 | E-GEOD-33791 | biostudies-arrayexpress
Project description:DNA base damage is an important contributor to genome instability, but how the formation and repair of these lesions is affected by the genomic landscape is unknown. Here we describe genome-wide maps of DNA base damage, repair, and mutagenesis at single nucleotide resolution in yeast treated with the alkylating agent methyl methanesulfonate (MMS). Analysis of these maps revealed that base excision repair (BER) of alkylation damage is significantly modulated by chromatin, with faster repair in nucleosome free regions, and slower repair and higher mutation density within strongly positioned nucleosomes. Both the translational and rotational settings of lesions within nucleosomes significantly influence BER efficiency; moreover, this effect is asymmetric relative to the nucleosome dyad and is regulated by histone modifications. Our data also indicate that MMS-induced A mutations are significantly enriched on the non-transcribed strand (NTS) of yeast genes, particularly in BER-deficient strains, due to higher damage formation on the NTS and transcription-coupled repair of the transcribed strand (TS). These findings reveal the influence of chromatin on repair and mutagenesis of base lesions on a genome-wide scale, and suggest a novel mechanism for transcription-associated mutation asymmetry, which is frequently observed in human cancers.
2017-08-10 | GSE98031 | GEO
Project description:Aberrant RNA methylation triggers recruitment of an alkylation repair complex
| PRJNA663914 | ENA
Project description:The activating E2F-transcription factors are best known for their dependence on the Retinoblastoma protein and their role in cellular proliferation. E2F3 is uniquely amplified in specific human tumours where its expression is inversely correlated with the survival of patients. Here, E2F3 interaction partners were identified by mass spectrometric analysis. We show that the SNF2-like HELLS interacts with E2F3 in vivo and cooperates with its oncogenic functions. Depletion of HELLS severely perturbs the induction of E2F-target genes, hinders cell cycle re-entry and growth. Using chromatin immmunoprecipitation coupled to sequencing we identified genome-wide targets of HELLS and E2F3. Our analysis revealed that HELLS binds near promoters of active genes, including the trithorax-related MLL1, and co-regulates E2F3-dependent genes. Our analysis is the first to link HELLS with E2F-controlled processes that are critical to establish a proliferative tumour circuitry. Strikingly, just as E2F3, HELLS is overexpressed in human tumours including prostate cancer, indicating that either factor may contribute to the malignant progression of tumours. Our work reveals that HELLS is important for E2F3 in tumour cell proliferation.
2011-12-19 | GSE33791 | GEO
Project description:Analysis of alkylation damage formation and base excision repair at yeast transcription factor binding sites
| PRJNA761418 | ENA
Project description:Chromatin barriers prevent spurious interactions between regulatory elements and DNA-binding proteins. One such barrier, whose mechanism for overcoming is poorly understood, is access to recombination hotspots during meiosis. Here we identify that the DNA-binding protein PRDM9 and chromatin remodeler HELLS function together to open chromatin at hotspots providing access to the DNA double-strand break (DSB) machinery. Recombination hotspots are decorated by a unique combination of histone modifications, not found at other regulatory elements. HELLS is recruited by PRDM9, and is necessary for both histone modification and DNA accessibility at hotspots. In male mice lacking HELLS, DSBs are retargeted to other sites of open chromatin, leading to germ cell death and sterility. Together, these data provide a model for hotspot activation where HELLS and PRDM9 function as a pioneer complex to create a unique epigenomic environment to open chromatin in preparation for proper placement and repair of DSBs.
2019-12-17 | GSE135896 | GEO
Project description:Osteoclasts are bone-resorbing cells essential for skeletal remodeling. The chromatin remodeler Hells has been implicated in epigenetic regulation during cellular differentiation, but its role in osteoclastogenesis remains unclear. To investigate the function of Hells in osteoclast differentiation, we performed RNA sequencing of bone marrow-derived macrophages (BMMs) treated with RANKL, with or without siRNA-mediated knockdown of Hells. This dataset provides transcriptomic profiles of Hells-deficient and control osteoclast precursors, offering insight into the epigenetic control of osteoclastogenesis.
2025-08-01 | GSE303340 | GEO