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Updated: Jan 13, 2026

Two- and Three-Dimensional Live Cell Imaging of DNA Damage Response Proteins
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Two- and Three-Dimensional Live Cell Imaging of DNA Damage Response Proteins

Published on: September 28, 2012

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APOBEC3C coordinates DDX5 in R-loop resolution and dynamic control of Chk1-mediated stress-responsive circuitry as a

Li Tao1,2, Yang Zhao3,4, Zhuangzhaung Jiang3,5

  • 1Department of Pharmacy, College of Medicine, Yangzhou University, Yangzhou, Jiangsu, China. imlitao@yzu.edu.cn.

Cell Death & Disease
|January 7, 2026
PubMed

Insights

The APOBEC3C (A3C) protein and DDX5 RNA helicase form a complex that promotes gemcitabine resistance in cancer by modulating DNA replication and damage responses. This A3C/DDX5/R-loop complex impairs cancer cell sensitivity to gemcitabine.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genomics

Background:

  • Genomic instability is a key feature of cancer, driven by alterations like those from APOBEC3 enzymes.
  • R-loops, RNA-DNA hybrids, disrupt cellular processes and are implicated in cancer progression.
  • APOBEC3C (A3C) is upregulated in response to gemcitabine, contributing to drug resistance, but its mechanisms are unclear.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which APOBEC3C (A3C) confers gemcitabine resistance in checkpoint-deficient tumors.
  • To identify regulatory circuitries involving A3C in cancer chemoresistance.
  • To investigate the role of A3C in DNA replication stress and repair pathways.

Main Methods:

  • Screening for A3C as a p53 transcriptional target.
  • In vitro and in vivo experiments using p53-deficient H1299 cells with A3C.
  • Assessing S-phase checkpoint activation and replication fork progression.
  • Pull-down assays and proteomic analysis to identify A3C interacting partners.
  • Investigating the role of DDX5 in R-loop resolution and gemcitabine sensitivity.

Main Results:

  • A3C expression in p53-deficient cells conferred gemcitabine resistance.
  • A3C enhanced Chk1-dependent S-phase checkpoint activation, slowing replication and aiding DNA repair.
  • A3C specifically interacted with RNA helicase DDX5, a key player in R-loop resolution.
  • DDX5 antagonized A3C's effect by attenuating Chk1 activation.
  • DDX5 knockdown in A3C-expressing cells enhanced gemcitabine-induced Chk1 activation and sensitivity via R-loop accumulation.

Conclusions:

  • The A3C/DDX5/R-loop complex impairs gemcitabine sensitivity by modulating Chk1 dynamics and DNA replication/damage responses.
  • A3C contributes to chemoresistance through interaction with DDX5 and regulation of R-loop homeostasis.
  • Understanding this complex offers potential therapeutic strategies to overcome gemcitabine resistance.

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