Taking the time to make important decisions: the checkpoint effector kinases Chk1 and Chk2 and the DNA damage response

Abstract

The cellular DNA damage response (DDR) is activated by many types of DNA lesions. Upon recognition of DNA damage by sensor proteins, an intricate signal transduction network is activated to coordinate diverse cellular outcomes that promote genome integrity. Key components of the DDR in mammalian cells are the checkpoint effector kinases Chk1 and Chk2 (referred to henceforth as the effector kinases; orthologous to spChk1 and spCds1 in the fission yeast S. pombe and scChk1 and scRad53 in the budding yeast S. cerevisiae). These evolutionarily conserved and structurally divergent kinases phosphorylate numerous substrates to regulate the DDR. This review will focus on recent advances in our understanding of the structure, regulation, and functions of the effector kinases in the DDR, as well as their potential roles in human disease.

Figure 1. The Checkpoint Kinases

Domain organization of the human Chk1 and Chk2 and the yeast spCds1 and scRad53 kinases are shown. The forkhead associated domains (FHA), SQ/TQ clusters (SCD), and kinase domains (Kinase) are indicated. (A) Mutations in Chk2 identified in human cancers are shown in bold-italic type. Phosphorylation sites identified to date are indicated. (B) spCds1 shares a similar domain organization as human Chk2 with T11 corresponding to the major damage inducible site T68 in Chk2. (C) Schematic of scRad53 domain organization and phosphorylation sites. The putative bipartite nuclear localization signal (NLS) is indicated. (D) Schematic of human Chk1 with domains labeled as in (A).

Figure 2. The Effector Kinases in the DDR

Regulators of effector kinase activation are shown in green. Known substrates and interacting proteins are shown in light blue with some regulatory proteins in tan. Shaded regions indicate some known functions of the proteins and are provided as an organizing principle and are not meant to exclude potential roles of any proteins in additional processes.