Transformation/transcription domain-associated protein (TRRAP)-mediated regulation of Wee1.
The G2 DNA damage checkpoint inhibits Cdc2 and mitotic entry through the dual regulation of Wee1 and Cdc25 by the Chk1 effector kinase. Upregulation of Chk1 by mutation or overexpression bypasses the requirement for upstream regulators or DNA damage to promote a G2 cell cycle arrest. We screened in fission yeast for mutations that rendered cells resistant to overexpressed chk1(+). We identified a mutation in tra1, which encodes one of two homologs of transformation/transcription domain-associated protein (TRRAP), an ATM/R-related pseudokinase that scaffolds several histone acetyltransferase (HAT) complexes. Inhibition of histone deacetylases reverts the resistance to overexpressed chk1(+), suggesting this phenotype is due to a HAT activity, although expression of checkpoint and cell cycle genes is not greatly affected. Cells with mutant or deleted tra1 activate Chk1 normally and are checkpoint proficient. However, these cells are semi-wee even when overexpressing chk1(+) and accumulate inactive Wee1 protein. The changed division response (Cdr) kinases Cdr1 and Cdr2 are negative regulators of Wee1, and we show that they are required for the Tra1-dependent alterations to Wee1 function. This identifies Tra1 as another component controlling the timing of entry into mitosis via Cdc2 activation.
Calonge
Teresa M
TM
Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA.
Eshaghi
Majid
M
Liu
Jianhua
J
Ronai
Ze'ev
Z
O'Connell
Matthew J
MJ
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D000071877:Checkpoint Kinase 1; D004789:Enzyme Activation / Q000187:drug effects; D016195:G2 Phase / Q000187:drug effects; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000494:pharmacology; D008938:Mitosis / Q000187:drug effects; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D012568:Schizosaccharomyces / Q000166:cytology / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000378:metabolism*; D013489:Suppression, Genetic / Q000187:drug effects
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D009687:Nuclear Proteins; D029702:Schizosaccharomyces pombe Proteins; C113829:transformation-transcription domain-associated protein; C012589:trichostatin A; D011494:Protein Kinases; C068689:wee1 protein, S pombe; D011505:Protein-Tyrosine Kinases; D000071877:Checkpoint Kinase 1; C000605873:Chk1 protein, S pombe