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Cdk1-interacting protein Cip1 is regulated by the S phase checkpoint in response to genotoxic stress

Ze Zhang1,2, Ping Ren3, Ajay A Vashisht4

  • 1College of Life Sciences, Hebei Agricultural University, Baoding, Hebei, 071001, China.

Genes to Cells : Devoted to Molecular & Cellular Mechanisms
|August 4, 2017
PubMed

Insights

The S phase checkpoint in yeast utilizes Mec1 and Rad53 to regulate Cip1 accumulation during replication stress, preserving genomic stability. This study reveals Cip1

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • Eukaryotic cells possess an S phase checkpoint to maintain genomic stability during DNA replication.
  • In budding yeast (Saccharomyces cerevisiae), Mec1 (an ATM/ATR homolog) and Rad53 (a Chk2 homolog) are key kinases in the DNA damage response.
  • Cip1 is a recently identified cyclin-dependent kinase inhibitor (CKI).

Purpose of the Study:

  • To investigate the regulation of Cip1 by the S phase checkpoint in response to genotoxic stress.
  • To elucidate the role of Cip1 in maintaining cell viability under replication stress.

Main Methods:

  • Investigated Cip1 accumulation and phosphorylation in response to genotoxic stress.
  • Utilized Mec1 and Rad53 deletion mutants to assess their role in Cip1 regulation.
  • Examined the effect of Cip1 deletion on cell proliferation under hydroxyurea treatment.
  • Assessed the interaction between Cip1 and G1 cyclin CLN2 dosage.

Main Results:

  • Cip1 accumulates significantly in a Mec1- and Rad53-dependent manner during replication stress.
  • Cip1 stabilization requires de novo protein synthesis and Mec1-dependent phosphorylation.
  • Deletion of Cip1 impairs proliferation, especially when G1 cyclin CLN2 dosage is increased, suggesting a role as a CKI.
  • Cip1 is placed under the control of the S phase checkpoint.

Conclusions:

  • Cip1 is a novel component of the S phase checkpoint response to genotoxic stress.
  • Cip1 plays a crucial role in preserving cell viability when chromosome replication is threatened.
  • Cip1 functions as a G1-cyclin-dependent kinase inhibitor within the S phase checkpoint pathway.

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