RPA shields inherited DNA lesions for post-mitotic DNA synthesis

Nat Commun. 2021 Jun 22;12(1):3827. doi: 10.1038/s41467-021-23806-5.

Abstract

The paradigm that checkpoints halt cell cycle progression for genome repair has been challenged by the recent discovery of heritable DNA lesions escaping checkpoint control. How such inherited lesions affect genome function and integrity is not well understood. Here, we identify a new class of heritable DNA lesions, which is marked by replication protein A (RPA), a protein primarily known for shielding single-stranded DNA in S/G2. We demonstrate that post-mitotic RPA foci occur at low frequency during unperturbed cell cycle progression, originate from the previous cell cycle, and are exacerbated upon replication stress. RPA-marked inherited ssDNA lesions are found at telomeres, particularly of ALT-positive cancer cells. We reveal that RPA protects these replication remnants in G1 to allow for post-mitotic DNA synthesis (post-MiDAS). Given that ALT-positive cancer cells exhibit high levels of replication stress and telomere fragility, targeting post-MiDAS might be a new therapeutic opportunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle / genetics
  • Cell Line
  • Cell Line, Tumor
  • DNA / genetics*
  • DNA / metabolism
  • DNA Damage
  • DNA Repair
  • DNA Replication / genetics*
  • HeLa Cells
  • Humans
  • Microscopy, Confocal
  • Mitosis / genetics*
  • Replication Protein A / genetics*
  • Replication Protein A / metabolism
  • Telomere / genetics
  • Telomere / metabolism
  • Time-Lapse Imaging / methods
  • Tumor Suppressor p53-Binding Protein 1 / genetics
  • Tumor Suppressor p53-Binding Protein 1 / metabolism

Substances

  • Replication Protein A
  • Tumor Suppressor p53-Binding Protein 1
  • DNA