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RNA demethylase ALKBH5 regulates cell cycle progression in DNA damage response

Bo Gao1, Haitao Pan1, Xiaoling Zhou2

  • 1Shaoxing Maternity and Child Health Care Hospital, Shaoxing, 312000, China.

Scientific Reports
|May 9, 2025
PubMed

Insights

The m6A demethylase ALKBH5 regulates DNA damage response and cell cycle arrest after X-ray exposure. Its depletion reduces DNA damage and promotes repair by upregulating cyclin-dependent kinase inhibitors.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Cell Biology

Background:

  • RNA N6-methyladenosine (m6A) modification is vital for DNA damage response.
  • The precise mechanisms underlying m6A's role in DNA damage are not fully understood.

Purpose of the Study:

  • To investigate the role of the m6A demethylase ALKBH5 in the cellular response to X-ray-induced DNA damage.
  • To elucidate the molecular mechanisms by which ALKBH5 influences DNA damage repair and cell cycle regulation.

Main Methods:

  • Depletion of ALKBH5 using knockdown techniques.
  • RNA sequencing and m6A sequencing to analyze gene expression and m6A modification patterns.
  • Cell cycle analysis (G2/M phase arrest) and apoptosis assays.

Main Results:

  • ALKBH5 depletion decreased X-ray-induced DNA damage and cell apoptosis.
  • ALKBH5 knockdown led to increased G2/M phase arrest.
  • ALKBH5 was found to remove m6A modifications from target mRNAs, suppressing their expression.
  • Knockdown of ALKBH5 increased the stability and expression of mRNAs encoding cyclin-dependent kinase inhibitors (e.g., CDKN1A, CDKN2B).
  • Upregulation of CDKN1A and CDKN2B contributed to G2/M phase arrest and DNA repair.

Conclusions:

  • ALKBH5 plays a significant role in the epigenetic regulation of the cell cycle checkpoint following X-ray-induced DNA damage.
  • ALKBH5 influences DNA repair pathways by modulating the expression of key cell cycle regulators.
  • ALKBH5 represents a potential therapeutic target for enhancing DNA damage-based cancer therapies.
Keywords:
ALKBH5Cell cycleDNA damage responsem6AmRNA stability

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