53BP1 Mediates ATR-Chk1 Signaling and Protects Replication Forks under Conditions of Replication Stress

Mol Cell Biol. 2018 Mar 29;38(8):e00472-17. doi: 10.1128/MCB.00472-17. Print 2018 Apr 15.

Abstract

Complete replication of the genome is an essential prerequisite for normal cell division, but a variety of factors can block the replisome, triggering replication stress and potentially causing mutation or cell death. The cellular response to replication stress involves recruitment of proteins to stabilize the replication fork and transmit a stress signal to pause the cell cycle and allow fork restart. We find that the ubiquitously expressed DNA damage response factor 53BP1 is required for the normal response to replication stress. Using primary, ex vivo B cells, we showed that a population of 53BP1-/- cells in early S phase is hypersensitive to short-term exposure to three different agents that induce replication stress. 53BP1 localizes to a subset of replication forks following induced replication stress, and an absence of 53BP1 leads to defective ATR-Chk1-p53 signaling and caspase 3-mediated cell death. Nascent replicated DNA additionally undergoes degradation in 53BP1-/- cells. These results show that 53BP1 plays an important role in protecting replication forks during the cellular response to replication stress, in addition to the previously characterized role of 53BP1 in DNA double-strand break repair.

Keywords: 53BP1; cancer biology; cell cycle; replication.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins / genetics
  • B-Lymphocytes / physiology
  • Caspase 3 / genetics
  • Cell Cycle Proteins / genetics
  • Cell Death / genetics
  • Cell Division / genetics
  • Cells, Cultured
  • Checkpoint Kinase 1 / genetics*
  • DNA / genetics
  • DNA Damage / genetics
  • DNA Repair / genetics
  • DNA Replication / genetics*
  • HEK293 Cells
  • Humans
  • Mice
  • S Phase / genetics
  • Signal Transduction / genetics
  • Tumor Suppressor p53-Binding Protein 1 / genetics*

Substances

  • Cell Cycle Proteins
  • Trp53bp1 protein, mouse
  • Tumor Suppressor p53-Binding Protein 1
  • DNA
  • Atr protein, mouse
  • Ataxia Telangiectasia Mutated Proteins
  • Checkpoint Kinase 1
  • Chek1 protein, mouse
  • Caspase 3