Evolutionary Conservation of a Novel Splice Variant of the Cds1/CHK2 Checkpoint Kinase Restricted to its Regulatory Domain

The Cds1/CHK2 kinase plays a key role in the activation of the G(2) checkpoint after DNA damage. Here we report the existence in fission yeast of a short variant (Sv) of Cds1 that is produced through an alternative splicing mechanism leading to a frame shift and premature termination. This SvCds1 protein consists solely of the regulatory region and lacks the catalytic domain. Expression of SvCds1 increases sensitivity to ionizing radiation and, to a lesser extent, to hydroxyurea, but not to UV radiation. We also report that in the human orthologue of Cds1, CHK2, differential splicing of a cryptic exon leads to a frame shift and premature termination producing a short variant (SvCHK2). Thus, we have discovered the existence of an evolutionary conserved mechanism ensuring the production of a catalytically inactive variant Cds1/CHK2 that is restricted to SQTQ and FHA domains and that can act as a dominant negative. The role that this short variant of Cds1/CHK2 might play in the response to DNA damage and the physiopathological consequences are discussed.