An intrinsic S/G 2 checkpoint enforced by ATR

Science. 2018 Aug 24;361(6404):806-810. doi: 10.1126/science.aap9346.

Abstract

The cell cycle is strictly ordered to ensure faithful genome duplication and chromosome segregation. Control mechanisms establish this order by dictating when a cell transitions from one phase to the next. Much is known about the control of the G1/S, G2/M, and metaphase/anaphase transitions, but thus far, no control mechanism has been identified for the S/G2 transition. Here we show that cells transactivate the mitotic gene network as they exit the S phase through a CDK1 (cyclin-dependent kinase 1)-directed FOXM1 phosphorylation switch. During normal DNA replication, the checkpoint kinase ATR (ataxia-telangiectasia and Rad3-related) is activated by ETAA1 to block this switch until the S phase ends. ATR inhibition prematurely activates FOXM1, deregulating the S/G2 transition and leading to early mitosis, underreplicated DNA, and DNA damage. Thus, ATR couples DNA replication with mitosis and preserves genome integrity by enforcing an S/G2 checkpoint.

Publication types

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

MeSH terms

  • Antigens, Surface / metabolism
  • Ataxia Telangiectasia Mutated Proteins / genetics
  • Ataxia Telangiectasia Mutated Proteins / physiology
  • Cyclin B1 / antagonists & inhibitors
  • Cyclin B1 / metabolism
  • DNA Damage / genetics
  • DNA Replication / genetics
  • Forkhead Box Protein M1 / metabolism
  • G2 Phase / genetics*
  • Gene Regulatory Networks
  • HCT116 Cells
  • Humans
  • Mitosis / genetics*
  • Phosphorylation
  • S Phase / genetics*
  • Telomerase

Substances

  • Antigens, Surface
  • Cyclin B1
  • ETAA1 protein, human
  • FOXM1 protein, human
  • Forkhead Box Protein M1
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Telomerase