HAT cofactor Trrap regulates the mitotic checkpoint by modulation of Mad1 and Mad2 expression.
As a component of chromatin-modifying complexes with histone acetyltransferase (HAT) activity, TRRAP has been shown to be involved in various cellular processes including gene transcription and oncogenic transformation. Inactivation of Trrap, the murine ortholog of TRRAP, in mice revealed its function in development and cell cycle progression. However, the underlying mechanism is unknown. Here, we show that the loss of Trrap in mammalian cells leads to chromosome missegregation, mitotic exit failure and compromised mitotic checkpoint. These mitotic checkpoint defects are caused by defective Trrap-mediated transcription of the mitotic checkpoint proteins Mad1 and Mad2. The mode of regulation by Trrap involves acetylation of histones H4 and H3 at the gene promoter of these mitotic players. Trrap associated with the HAT Tip60 and PCAF at the Mad1 and Mad2 promoters in a cell cycle-dependent manner and Trrap depletion abolished recruitment of these HATs. Finally, ectopic expression of Mad1 and Mad2 fully restores the mitotic checkpoint in Trrap-deficient cells. These results demonstrate that Trrap controls the mitotic checkpoint integrity by specifically regulating Mad1 and Mad2 genes.
Li
Hai
H
Group of Gene-Environment Biology, International Agency for Research on Cancer (IARC), Lyon, France.
Cuenin
Cyrille
C
Murr
Rabih
R
Wang
Zhao-Qi
ZQ
Herceg
Zdenko
Z
D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D020090:Chromosome Segregation; D019926:Cyclin B / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D005786:Gene Expression Regulation; D018816:Genes, cdc; D051548:Histone Acetyltransferases; D006657:Histones / Q000378:metabolism; D006801:Humans; D064246:Mad2 Proteins; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D019926:Cyclin B; D006657:Histones; C501384:MAD1L1 protein, human; C501385:Mad1l1 protein, mouse; D064246:Mad2 Proteins; C577698:Mad2l1 protein, mouse; C577699:Mad2l2 protein, mouse; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; C113829:transformation-transcription domain-associated protein; D000123:Acetyltransferases; D051548:Histone Acetyltransferases