Mechanisms of loading and release of the 9-1-1 checkpoint clamp

Nat Struct Mol Biol. 2022 Apr;29(4):369-375. doi: 10.1038/s41594-022-00741-7. Epub 2022 Mar 21.

Abstract

Single-stranded or double-stranded DNA junctions with recessed 5' ends serve as loading sites for the checkpoint clamp, 9-1-1, which mediates activation of the apical checkpoint kinase, ATRMec1. However, the basis for 9-1-1's recruitment to 5' junctions is unclear. Here, we present structures of the yeast checkpoint clamp loader, Rad24-replication factor C (RFC), in complex with 9-1-1 and a 5' junction and in a post-ATP-hydrolysis state. Unexpectedly, 9-1-1 adopts both closed and planar open states in the presence of Rad24-RFC and DNA. Moreover, Rad24-RFC associates with the DNA junction in the opposite orientation of processivity clamp loaders with Rad24 exclusively coordinating the double-stranded region. ATP hydrolysis stimulates conformational changes in Rad24-RFC, leading to disengagement of DNA-loaded 9-1-1. Together, these structures explain 9-1-1's recruitment to 5' junctions and reveal new principles of sliding clamp loading.

Publication types

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

MeSH terms

  • Adenosine Triphosphate
  • Cell Cycle Proteins
  • DNA / chemistry
  • DNA Replication
  • Intracellular Signaling Peptides and Proteins
  • Replication Protein C / genetics
  • Replication Protein C / metabolism
  • Saccharomyces cerevisiae Proteins* / metabolism
  • Saccharomyces cerevisiae* / metabolism

Substances

  • Cell Cycle Proteins
  • Intracellular Signaling Peptides and Proteins
  • RAD24 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Adenosine Triphosphate
  • DNA
  • Replication Protein C