A novel human p53 isoform is an essential element of the ATR-intra-S phase checkpoint.
The archetypal human tumor suppressor p53 is considered to have unique transactivation properties. The assumption is based on the fact that additionally identified human p53 isoforms lack transcriptional activity. However, we provide evidence for the existence of an alternatively spliced p53 isoform (Deltap53) that exerts its transcriptional activity independent from p53. In contrast to p53, Deltap53 transactivates the endogenous p21 and 14-3-3sigma but not the mdm2, bax, and PIG3 promoter. Cell cycle studies showed that Deltap53 displays its differential transcriptional activity only in damaged S phase cells. Upon activation of the ATR-intra-S phase checkpoint, Deltap53, but not p53, transactivates the Cdk inhibitor p21. Induction of p21 results in downregulation of cyclin A-Cdk activity and accordingly attenuation of S phase progression. Data demonstrate that the Deltap53-p21-cyclin A-Cdk pathway is crucial to facilitate uncoupling of repair and replication events, indicating that Deltap53 is an essential element of the ATR-intra-S phase checkpoint.
Rohaly
Gabor
G
Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie, Universität Hamburg, Martinistrasse 52, D-20251, Hamburg, Germany.
Chemnitz
Jan
J
Dehde
Silke
S
Nunez
Alejandro Mena
AM
Heukeshoven
Jochen
J
Deppert
Wolfgang
W
Dornreiter
Irena
I
D017398:Alternative Splicing / Q000235:genetics / Q000528:radiation effects; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D006801:Humans; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects; D016196:S Phase / Q000235:genetics / Q000502:physiology* / Q000528:radiation effects; D020539:Sequence Analysis, Protein / Q000379:methods; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects; D014466:Ultraviolet Rays
D018797:Cell Cycle Proteins; D020033:Protein Isoforms; D016159:Tumor Suppressor Protein p53; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases