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.
Lemaire
Matthieu
M
LBCMCP-CNRS UMR5088, Université Paul Sabatier, IFR109 Institut d'Exploration Fonctionnelle des Génomes, Toulouse, France.
Prime
Joanna
J
Ducommun
Bernard
B
Bugler
Béatrix
B
D017398:Alternative Splicing / Q000235:genetics*; D000595:Amino Acid Sequence; D001483:Base Sequence; D002470:Cell Survival; D064447:Checkpoint Kinase 2; D018076:DNA, Complementary / Q000235:genetics; D004307:Dose-Response Relationship, Radiation; D019143:Evolution, Molecular; D005091:Exons / Q000235:genetics; D005720:Gamma Rays; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D007438:Introns / Q000235:genetics; D008969:Molecular Sequence Data; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011836:Radiation Tolerance; D012568:Schizosaccharomyces / Q000166:cytology / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D029702:Schizosaccharomyces pombe Proteins; D014466:Ultraviolet Rays
D018076:DNA, Complementary; D012333:RNA, Messenger; D029702:Schizosaccharomyces pombe Proteins; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; C578636:Cds1 protein, S pombe; D017346:Protein Serine-Threonine Kinases; D006918:Hydroxyurea