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LINE1 RNA demethylation represses chromatin accessibility and sensitizes cancer cells to blockage of DNA damage repair ChIP-seq

ABSTRACT: Repression of DNA damage repair by PARP inhibitors (PARPi) has shown great efficacy in cancer treatment. However, therapy resistance remains a significant clinical challenge. Here, we demonstrated that the N6-methyladenosine (m6A) modification of long interspersed nucleotide element-1 (LINE1, or L1) facilitates DNA damage repair in cancer cells, whereas removal of L1 m6A modifications enhances the sensitivity of both BRCA-wild-type and BRCA-mutant cells to PARPi. Specifically, following olaparib treatment, METTL3 accumulates on chromatin, which results in increased chromatin accessibility. Knockdown of METTL3 or removal of m6A on L1 RNAs increases METTL3 levels, leading to reduced chromatin accessibility. This, in turn, inhibits DNA end resection at damage sites and prevents PARP1 dissociation, ultimately impairing homologous recombination repair and enhancing tumor sensitivity to PARPi. Our findings unveil a novel regulatory mechanism of L1 m6A that governs the DNA damage repair response, providing a potential strategy of targeting METTL3 in combination with PARPi for cancer therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE285741 | GEO | 2026/04/30

REPOSITORIES: GEO

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LINE1 RNA demethylation represses chromatin accessibility and sensitizes cancer cells to blockage of DNA damage repair [ATAC-seq]

Project description:Repression of DNA damage repair by PARP inhibitors (PARPi) has shown great efficacy in cancer treatment. However, therapy resistance remains a significant clinical challenge. Here, we demonstrated that the N6-methyladenosine (m6A) modification of long interspersed nucleotide element-1 (LINE1, or L1) facilitates DNA damage repair in cancer cells, whereas removal of L1 m6A modifications enhances the sensitivity of both BRCA-wild-type and BRCA-mutant cells to PARPi. Specifically, following olaparib treatment, METTL3 accumulates on chromatin, which results in increased chromatin accessibility. Knockdown of METTL3 or removal of m6A on L1 RNAs increases H3K9me3 levels, leading to reduced chromatin accessibility. This, in turn, inhibits DNA end resection at damage sites and prevents PARP1 dissociation, ultimately impairing homologous recombination repair and enhancing tumor sensitivity to PARPi. Our findings unveil a novel regulatory mechanism of L1 m6A that governs the DNA damage repair response, providing a potential strategy of targeting METTL3 in combination with PARPi for cancer therapy.

2026-04-30 | GSE285742 | GEO

LINE1 RNA demethylation represses chromatin accessibility and sensitizes cancer cells to blockage of DNA damage repair [MeRIP-seq]

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A site-specific analysis of the ADP-Ribosylome unveils Homogeneous Serine ADP-Ribosylation across wild-type and BRCA-mutant Breast Cancer cell lines

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2024-08-02 | PXD047613 | Pride

KAT2B-Mediated Epigenetic Suppression of RAD51C Enhances Olaparib Sensitivity in Colorectal Cancer

Project description:By blocking poly ADP ribose polymerase (PARP), olaparib prevents DNA damage repair, particularly in tumors that have a BRCA1/2 mutation or are BRCA-positive. Nevertheless, a Phase II study of 33 CRC patients receiving mono-Olaparib therapy revealed that some of these individuals still had resistance to Olaparib while having poor DNA damage repair. RAD51 reversion mutations are a frequent cause of resistance to PARP inhibitors in cancers that do not have BRCA mutations. Though little is known, a number of tactics have been studied when combining PARPi with other inhibitors. Here, we introduce the enzyme KAT2B as a protein involved in transcription that is connected to RAD51C, reducing the levels of RAD51C by lowering the acetylation of Histone H3 (H3K27) at the beginning of the RAD51C gene. Consequently, colorectal cancer cells become more vulnerable to Olaparib therapy. The H3K27ac binding domain is necessary for the transcription of RAD51C. We find that a subpopulation of tumor cells expressing RAD51C have reduced endogenous KAT2B expression. This expression leads to increased DNA damage accumulation and decreased PARPi resistance in RAD51C-expressing cells. According to our findings, RAD51C-expressing cells' RAD51C and PARPi responses are significantly regulated by KAT2B and histone acetylation. This information offers vital new understandings into the molecular requirements for focusing on BRCA-functional malignancies.

2026-03-18 | GSE267911 | GEO

ALC1 and PARP activities coordinate chromatin accessibility and viability in homologous recombination deficient cells (RNA-seq)

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2020-12-02 | GSE149104 | GEO

ALC1 and PARP activities coordinate chromatin accessibility and viability in homologous recombination deficient cells (ATAC-seq)

2020-12-02 | GSE150955 | GEO

The N6-methylation of adenosine (m6A) in FZD10 mRNA contributes to PARP inhibitor resistance

Project description:Chemical modifications of RNAs have emerged as a new layer of epigenetic gene regulation. N6-methyladenosine (m6A) is the most abundant chemical modification of messenger RNA (mRNA). The m6A modification affects RNA fate and functions such as RNA stability. Despite the high initial response rates to PARP inhibitors in BRCA1/2-mutated epithelial ovarian cancers (EOC), PARP inhibitor (PARPi) resistance remains a major challenge. The role of m6A modification in PARPi resistance has not previously been explored. Here we show that m6A modification of FZD10 mRNA contributes to PARPi resistance by upregulating the Wnt/-catenin pathway in BRCA-mutated EOC cells. Global m6A profile reveals a significant increase in m6A modification in FZD10 mRNA. This correlates with an increase in FZD10 mRNA stability and an upregulation of the Wnt/-catenin pathway in PARPi resistant cells. FZD10 knockdown or inhibition of the Wnt/-catenin sensitizes the resistant cells to PARPi. Mechanistically, downregulation of m6A demethylases FTO and ALKBH5 is sufficient to increase FZD10 mRNA m6A modification and reduce PARPi sensitivity, which correlates with an increase in homologous recombination activity. Moreover, PAPRi and Wnt/-catenin inhibitor showed synergistic suppression of growth of PAPRi resistant cells both in vitro and in vivo in a xenograft ovarian cancer mouse model. Our results show that m6A contributes to PAPRi resistance in BRCA-deficient EOC cells by upregulating the Wnt/-catenin pathway through stabilizing FZD10. They also suggest that inhibition of Wnt/-catenin pathway represents a potential strategy to overcome PARPi resistance.

2019-09-14 | GSE119963 | GEO

Immunotherapy Utilizing NK cells and ADCC Mediating Agents with Poly (ADP-ribose) polymerase (PARP) Inhibition

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2018-12-11 | GSE121682 | GEO

Targeting STAT3-FoxO1 axis reverses de novo and acquired PARP inhibitor resistance independent of BRCA status. [Whole-genome seq]

Project description:PARP inhibition has been approved as a compelling strategy for treating multiple human cancers bearing homologous recombination defects (HRD). However, due to the lack of functional biomarkers of PARPi response beyond known genetic mutations in HRD genes, expanding the potential benefit of PARP inhibitors, as well as the identification of effective therapeutic strategies for treating PARPi-resistant cancers remain urgent unmet needs. Here, we report high levels of FoxO1, either at basal expression or upon induction by PARPi, render both BRCA-proficient (BP) and BRCA-deficient (BD) human cancers resistant to PAPRi via modulating transcriptomic signature regulating DNA damage response (DDR). We further elucidated that PARPi-induced STAT3 activation, which occurred through its attenuated dephosphorylation at Y705, resulted in enhanced FoxO1 transcription via recruiting TOP2A, a downstream target of FoxO1. TOP2A orchestrated STAT3-dependent transcriptional program via facilitating RNA Pol II recruitment to gene promoters, as well as promoter-proximal pausing and pause release. Intriguingly, STAT3 inhibitor exhibits a potent synergistic effect with PARPi in treating BP or BD PAPRi-resistant PDX models across cancer types. Our data highlight a potential role of FoxO1 serving as both predictive and prognostic marker for PARPi treatment, and reveal the potency of combination treatment strategy using STAT3 inhibitor with PARPi in sensitizing PARPi-resistant cancers, regardless of BRCA status.

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