Send to:

Choose Destination
See comment in PubMed Commons below
Proc Natl Acad Sci U S A. 2012 Jan 3;109(1):197-202. doi: 10.1073/pnas.1104767109. Epub 2011 Dec 19.

Checkpoint kinase 1 (Chk1)-short is a splice variant and endogenous inhibitor of Chk1 that regulates cell cycle and DNA damage checkpoints.

Author information

  • 1Department of Cellular Biology and Anatomy, Medical College of Georgia, Georgia Health Sciences University, Augusta, GA 30912, USA.


Checkpoint kinase 1 (Chk1) is a key regulator of checkpoint signaling in both the unperturbed cell cycle and DNA damage response. Under these conditions, Chk1 becomes active to prevent premature CDK1 activation and mitotic entry until DNA is properly replicated or repaired. It is unclear how Chk1 activity is controlled in the unperturbed cell cycle. During DNA damage, Chk1 is activated by ataxia telangiectasia and Rad3 related (ATR)-mediated phosphorylation; however, it is not entirely clear how this phosphorylation results in Chk1 activation. Here we report an N-terminally truncated alternative splice variant of Chk1, Chk1-S. Importantly, we show that Chk1-S is an endogenous repressor and regulator of Chk1. In the unperturbed cell cycle, Chk1-S interacts with and antagonizes Chk1 to promote the S-to-G2/M phase transition. During DNA damage, Chk1 is phosphorylated, which disrupts the Chk1-Chk1-S interaction, resulting in free, active Chk1 to arrest the cell cycle and facilitate DNA repair. Higher levels of Chk1-S are expressed, along with Chk1, in fetal and cancer tissues than in normal tissues. However, forced overexpression of Chk1-S in cultured cells and tumor xenografts induces premature mitotic entry, mitotic catastrophe, and reduction of tumor growth. The identification of Chk1-S as a unique splice variant and key regulator of Chk1 provides insights into cell cycle regulation and DNA damage response.

[PubMed - indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Write to the Help Desk