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ATR/Chk1 interacting lncRNA modulates DNA damage response to induce breast cancer chemoresistance

Rong Luo1,2,3, Jiannan Wu1,2, Xueman Chen1,2

  • 1Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.

Cell Insight
|August 16, 2024
PubMed

Insights

A newly identified long noncoding RNA, ACIL, activates the ATR-Chk1 pathway, promoting chemoresistance in breast cancer. Targeting ACIL may reverse resistance to DNA damaging drugs.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • The ATR-Chk1 pathway is crucial for DNA damage response.
  • The role of long noncoding RNAs (lncRNAs) in this pathway is largely unexplored.

Purpose of the Study:

  • To identify and characterize lncRNAs regulating the ATR-Chk1 pathway.
  • To investigate the role of ACIL in breast cancer chemoresistance.

Main Methods:

  • Identification of ATR and Chk1 interacting lncRNA (ACIL).
  • Assessing ACIL's effect on Chk1 phosphorylation and DNA damage response.
  • Evaluating ACIL levels in breast cancer patients and its correlation with treatment outcomes.
  • In vitro and in vivo studies of ACIL knockdown effects on chemoresistance.

Main Results:

  • ACIL promotes Chk1 phosphorylation by ATR upon DNA damage.
  • High ACIL levels correlate with chemoresistance and poor prognosis in breast cancer.
  • ACIL knockdown sensitizes breast cancer cells to DNA damaging agents.
  • ACIL protects cancer cells by inducing cell cycle arrest and stabilizing replication forks.

Conclusions:

  • ACIL represents a novel lncRNA-dependent mechanism for activating the ATR-Chk1 pathway.
  • ACIL is a potential predictive biomarker for chemotherapy sensitivity in breast cancer.
  • Targeting ACIL could be a therapeutic strategy to overcome chemoresistance.
Keywords:
ATRChemotherapy resistanceChk1DNA damage responseLong noncoding RNA

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