BRCA2-dependent maturation of nascent strands during DNA replication

  • Mol Cell. 2026 Apr 16;86(8):1427-1440.e5. doi: 10.1016/j.molcel.2026.03.012.
Larissa Milano  1 ,  Sophie Wells  2 ,  Alina Vaitsiankova  3 ,  Lylah Drummond-Clarke  2 ,  Xiaoxuan Zhu  4 ,  Aura Carreira  5 ,  Masato T Kanemaki  6 ,  Keith W Caldecott  7
Affiliations
  • 1. Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, UK. Electronic address: [email protected].
  • 2. Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, UK.
  • 3. Department of Genetics and Development, Institute for Cancer Genetics, Columbia University, New York, NY, USA.
  • 4. Department of Chromosome Science, National Institute of Genetics, Research Organization of Information and Systems (ROIS), Mishima, Shizuoka, Japan.
  • 5. Genome Instability and Cancer Predisposition Laboratory, Centro de Biologia Molecular "Severo Ochoa" (CBM), CSIC, UAM, Madrid, Spain.
  • 6. Department of Chromosome Science, National Institute of Genetics, Research Organization of Information and Systems (ROIS), Mishima, Shizuoka, Japan; Graduate Institute for Advanced Studies, SOKENDAI, Mishima, Shizuoka, Japan; Department of Biological Science, Graduate School of Science, the University of Tokyo, Bunkyo-ku, Tokyo, Japan.
  • 7. Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, UK. Electronic address: [email protected].
PMID: 41935526 DOI: 10.1016/j.molcel.2026.03.012
Abstract

A major source of poly(ADP-ribose) polymerase (PARP) activity in proliferating cells is unligated Okazaki fragments. Consequently, the anti-cancer PARP Inhibitor olaparib impedes the maturation of nascent DNA strand fragments during DNA replication. Here, we show that wild-type human cells overcome this impediment by triggering a process that facilitates nascent strand maturation in the presence of olaparib. We show that this process operates on very large nascent strand fragments and repairs thousands of olaparib-induced DNA single-strand breaks/gaps per genome. Critically, this process is dependent on the tumor suppressors BRCA1 and BRCA2 and is associated with the BRCA2-dependent accumulation of RAD51 recombinase in chromatin. Our data identify nascent strand gaps that are induced by olaparib independently of replication fork reversal and/or PRIMPOL-mediated repriming and that are repaired by a BRCA2-dependent process that we propose is daughter-strand gap protection and/or repair occurring hundreds of kilobases behind DNA replication forks.

Keywords
BRCA1; BRCA2; DNA replication; Okazaki fragment; PARP1; RAD51; gap protection; gap repair; homologous recombination; single-strand gaps.
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