Abro1 maintains genome stability and limits replication stress by protecting replication fork stability

  1. Bin Wang1,2
  1. 1Department of Genetics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
  2. 2Genes and Development Program, The University of Texas Graduate School of Biomedical Sciences, Houston, Texas 77030, USA;
  3. 3Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
  4. 4Department of Pediatrics, The University of Texas Medical School at Houston, Houston, Texas 77030, USA;
  5. 5Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA
  1. Corresponding author: bwang3{at}mdanderson.org
  1. 6 These authors contributed equally to this work.

Abstract

Protection of the stalled replication fork is crucial for responding to replication stress and minimizing its impact on chromosome instability, thus preventing diseases, including cancer. We found a new component, Abro1, in the protection of stalled replication fork integrity. Abro1 deficiency results in increased chromosome instability, and Abro1-null mice are tumor-prone. We show that Abro1 protects stalled replication fork stability by inhibiting DNA2 nuclease/WRN helicase-mediated degradation of stalled forks. Depletion of RAD51 prevents the DNA2/WRN-dependent degradation of stalled forks in Abro1-deficient cells. This mechanism is distinct from the BRCA2-dependent fork protection pathway, in which stable RAD51 filament formation prevents MRE11-dependent degradation of the newly synthesized DNA at stalled forks. Thus, our data reveal a new aspect of regulated protection of stalled replication forks that involves Abro1.

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Footnotes

  • Received March 22, 2017.
  • Accepted July 26, 2017.

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