Che-1 phosphorylation by ATM/ATR and Chk2 kinases activates p53 transcription and the G2/M checkpoint.
Che-1 is a RNA polymerase II-binding protein involved in the transcription of E2F target genes and induction of cell proliferation. Here we show that Che-1 contributes to DNA damage response and that its depletion sensitizes cells to anticancer agents. The checkpoint kinases ATM/ATR and Chk2 interact with Che-1 and promote its phosphorylation and accumulation in response to DNA damage. These Che-1 modifications induce a specific recruitment of Che-1 on the TP53 and p21 promoters. Interestingly, it has a profound effect on the basal expression of p53, which is preserved following DNA damage. Notably, Che-1 contributes to the maintenance of the G2/M checkpoint induced by DNA damage. These findings identify a mechanism by which checkpoint kinases regulate responses to DNA damage.
Bruno
Tiziana
T
Experimental Chemotherapy Laboratory, Department of Experimental Oncology, Regina Elena Cancer Institute, 00158 Rome, Italy.
De Nicola
Francesca
F
Iezzi
Simona
S
Lecis
Daniele
D
D'Angelo
Carmen
C
Di Padova
Monica
M
Corbi
Nicoletta
N
Dimiziani
Leopoldo
L
Zannini
Laura
L
Jekimovs
Christian
C
Scarsella
Marco
M
Porrello
Alessandro
A
Chersi
Alberto
A
Crescenzi
Marco
M
Leonetti
Carlo
C
Khanna
Kum Kum
KK
Soddu
Silvia
S
Floridi
Aristide
A
Passananti
Claudio
C
Delia
Domenico
D
Fanciulli
Maurizio
M
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000502:physiology*; D002455:Cell Division; D064447:Checkpoint Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000502:physiology*; D016195:G2 Phase; D016158:Genes, p53; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D012097:Repressor Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000502:physiology*
C402637:AATF protein, human; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; C578634:CHEK2 protein, human; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases