DDX11 loss causes replication stress and pharmacologically exploitable DNA repair defects

Jegadesan, Nanda Kuma and Branzei, Dana (2021). DDX11 loss causes replication stress and pharmacologically exploitable DNA repair defects. Proceedings of the National Academy of Sciences, 118(17), article no. e2024258118.

DOI: https://doi.org/10.1073/pnas.2024258118


DDX11 encodes an iron–sulfur cluster DNA helicase required for development, mutated, and overexpressed in cancers. Here, we show that loss of DDX11 causes replication stress and sensitizes cancer cells to DNA damaging agents, including poly ADP ribose polymerase (PARP) inhibitors and platinum drugs. We find that DDX11 helicase activity prevents chemotherapy drug hypersensitivity and accumulation of DNA damage. Mechanistically, DDX11 acts downstream of 53BP1 to mediate homology-directed repair and RAD51 focus formation in manners nonredundant with BRCA1 and BRCA2. As a result, DDX11 down-regulation aggravates the chemotherapeutic sensitivity of BRCA1/2-mutated cancers and resensitizes chemotherapy drug–resistant BRCA1/2-mutated cancer cells that regained homologous recombination proficiency. The results further indicate that DDX11 facilitates recombination repair by assisting double strand break resection and the loading of both RPA and RAD51 on single-stranded DNA substrates. We propose DDX11 as a potential target in cancers by creating pharmacologically exploitable DNA repair vulnerabilities.

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  • Item ORO ID
  • 81654
  • Item Type
  • Journal Item
  • ISSN
  • 0027-8424
  • Project Funding Details
  • Funded Project NameProject IDFunding Body
    ITN-SYNTRAIN682190European Eunion
    Italian Association for Cancer Research grantsIG 18976, IG 23710AIRC
  • Extra Information
  • Source data have been deposited in Mendeley (DOI: 10.17632/tz4z2syb2r.1)
  • Keywords
  • replication stress; homologous recombination; chemotherapy; BRCA1/2DDX11
  • Academic Unit or School
  • Faculty of Science, Technology, Engineering and Mathematics (STEM)
  • Research Group
  • Cancer Research Group
  • Copyright Holders
  • © PNAS
  • Depositing User
  • Nandakumar Jegadesan