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Updated: Mar 28, 2026

Characterizing DNA Repair Processes at Transient and Long-lasting Double-strand DNA Breaks by Immunofluorescence Microscopy
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The BRCA1-A complex restricts replication fork reversal-dependent DNA repair in ATM deficient cells

Arindam Datta1, Jessica Jackson2, Yaroslav I Morozov1

  • 1Department of Cancer Biology, Penn Center for Genome Integrity, Basser Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.

Biorxiv : the Preprint Server for Biology
|March 27, 2026
PubMed

Insights

Ataxia Telangiectasia Mutated (ATM) kinase deficiency causes cancer and drug sensitivity. Our study shows BRCA1-A complex loss restores drug resistance in ATM-deficient cells by enabling DNA repair pathways.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • Ataxia Telangiectasia Mutated (ATM) kinase deficiency is linked to cancer susceptibility and heightened sensitivity to certain chemotherapies.
  • The BRCA1-interacting A (BRCA1-A) complex and the XRCC4/Ligase 4 complex play roles in DNA repair pathways, influencing drug resistance in ATM-deficient cells.

Purpose of the Study:

  • To investigate the role of ATM inhibition and the BRCA1-A complex in DNA damage response and drug sensitivity.
  • To elucidate the mechanisms by which BRCA1-A influences the recognition of damaged replication forks and subsequent DNA repair.

Main Methods:

  • Utilized ATM inhibition models in cancer cells.
  • Investigated SUMO and ubiquitin-mediated signaling at damaged replication forks.
  • Assessed chromatin accessibility, nuclease activity, and DNA end-resection.
  • Employed electron microscopy to visualize replication fork dynamics.

Main Results:

  • ATM inhibition triggers SUMO/ubiquitin-mediated BRCA1-A recognition of damaged forks, restricting end-resection and increasing Topoisomerase I inhibitor sensitivity.
  • BRCA1-A deficient cells exhibit increased chromatin accessibility and nuclease activity, leading to restored resection and drug resistance.
  • ATM inhibition blocks replication fork reversal, a process restored by BRCA1-A loss, generating substrates for end resection.

Conclusions:

  • BRCA1-A enforces a restrictive chromatin state that prevents the formation of DNA end-resection substrates.
  • Replication fork reversal is a critical determinant of chemotherapy response in ATM-deficient cells.
  • Targeting the BRCA1-A pathway could offer new therapeutic strategies for ATM-deficient cancers.

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