DDX11 loss causes replication stress and pharmacologically exploitable DNA repair defects

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Nanda Kumar Jegadesan1, Dana Branzei2,3

  • 1The FIRC Institute of Molecular Oncology, Italian Foundation for Cancer Research, 20139, Milan, Italy.

Proceedings of the National Academy of Sciences of the United States of America
|April 21, 2021
PubMed

Insights

Loss of DDX11 DNA helicase causes replication stress, increasing cancer cell sensitivity to chemotherapy. DDX11 is crucial for DNA repair, making it a potential therapeutic target in various cancers.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Genetics

Background:

  • DDX11 encodes an iron-sulfur cluster DNA helicase essential for development.
  • Mutations and overexpression of DDX11 are observed in various cancers.
  • DDX11 plays a role in DNA replication and repair.

Purpose of the Study:

  • To investigate the role of DDX11 in DNA repair and its impact on cancer cell sensitivity to DNA damaging agents.
  • To elucidate the mechanism by which DDX11 influences DNA repair pathways.
  • To evaluate DDX11 as a potential therapeutic target in cancer treatment.

Main Methods:

  • Functional assays to assess replication stress and DNA damage accumulation.
  • Analysis of homology-directed repair (HDR) and RAD51 focus formation.
  • Investigating DDX11's role in double-strand break resection and RPA/RAD51 loading.

Main Results:

  • Loss of DDX11 induces replication stress and sensitizes cancer cells to PARP inhibitors and platinum drugs.
  • DDX11's helicase activity is critical for preventing hypersensitivity to chemotherapy and DNA damage.
  • DDX11 acts downstream of 53BP1, mediating HDR and RAD51 focus formation independently of BRCA1/2.
  • DDX11 down-regulation exacerbates sensitivity in BRCA1/2-mutated cancers and resensitizes resistant cells.

Conclusions:

  • DDX11 is essential for efficient homologous recombination repair by facilitating DNA resection and stabilizing RPA/RAD51 on ssDNA.
  • DDX11 deficiency creates pharmacologically exploitable DNA repair vulnerabilities in cancer.
  • Targeting DDX11 may offer a novel therapeutic strategy for cancers, particularly those with BRCA1/2 mutations.
Keywords:
BRCA1/2DDX11chemotherapyhomologous recombinationreplication stress

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