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LINE1 RNA demethylation sensitizes cancer cells to PARPi through global chromatin remodeling

Zihong Kang1,2, Ruimeng Li3, Lei Xu4

  • 1State Key Laboratory of Gene Function and Modulation Research, School of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China.

Genome Biology
|May 8, 2026
PubMed
Abstract

Insights

Targeting N6-methyladenosine (m6A) modification on LINE1 (L1) retrotransposons can overcome PARP inhibitor (PARPi) resistance in cancer. Removing L1 m6A enhances cancer cell sensitivity to PARPi by impairing DNA repair.

Area of Science:

  • Cancer Biology
  • Epigenetics
  • DNA Damage Response

Background:

  • PARP inhibitors (PARPi) are effective cancer treatments, but therapy resistance is a major obstacle.
  • Understanding resistance mechanisms is crucial for improving cancer therapy outcomes.

Purpose of the Study:

  • To investigate the role of N6-methyladenosine (m6A) modification in LINE1 (L1) retrotransposons in cancer therapy resistance.
  • To explore novel strategies for overcoming PARPi resistance.

Main Methods:

  • Analysis of m6A modification on L1 retrotransposons in cancer cells.
  • Investigating the impact of METTL3, an m6A writer, on chromatin accessibility and DNA repair.
  • Assessing the sensitivity of BRCA-wild-type and BRCA-mutant cells to PARPi following modulation of L1 m6A.

Main Results:

  • m6A modification of L1 facilitates DNA damage repair in cancer cells.
  • Removal of L1 m6A modifications increases sensitivity to PARPi in both BRCA-wild-type and BRCA-mutant cells.
  • METTL3 accumulation on chromatin increases accessibility; its knockdown or L1 m6A removal reduces accessibility, impairs DNA repair, and enhances PARPi sensitivity.

Conclusions:

  • L1 m6A modification is a novel regulator of the DNA damage repair response.
  • Targeting METTL3 in combination with PARPi presents a potential therapeutic strategy for cancer treatment.
Keywords:
H3K9me3 modificationHR repairLINE1 RNA methylationPARPi sensitivity

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