RESUMO
UHRF2 is a ubiquitin-protein ligase E3 that regulates cell cycle, genomic stability and epigenetics. We conducted a co-immunoprecipitation assay and found that TIP60 and HDAC1 interact with UHRF2. We previously demonstrated that UHRF2 regulated H3K9ac and H3K14ac differentially in normal and cancer cells. However, the accurate signal transduction mechanisms were not clear. In this study, we found that TIP60 acted downstream of UHRF2 to regulate H3K9ac and H3K14ac expression. TIP60 is stabilized in normal cells by UHRF2 ubiquitination. However, TIP60 is destabilized in cancer cells. Depletion or inhibition of TIP60 disrupts the regulatory relationship between UHRF2, H3K9ac and H3K14ac. In summary, the findings suggest that UHRF2 mediated the post-translational modification of histones and the initiation and progression of cancer.
Assuntos
Humanos , Linhagem Celular , Histona Acetiltransferases , Genética , Metabolismo , Histonas , Genética , Metabolismo , Lisina Acetiltransferase 5 , Proteínas de Neoplasias , Genética , Metabolismo , Neoplasias , Genética , Metabolismo , Domínios RING Finger , Ubiquitina-Proteína Ligases , Genética , Metabolismo , UbiquitinaçãoRESUMO
Over the last decade, great progress has been made in elucidating how the human genome operates in the chromatin context. This paper describes our work on two human acetyltransferases, PCAF and TIP60, and their interaction partners. This study provides new clues on the function of these enzymes. In a striking parallel with the general transcription factor TFIID, PCAF complex contains proteins that have histone-like domains. We speculate that these subunits can presumably form a nucleosome-like structure on DNA, which would allow PCAF to contribute to the maintenance of an active state of chromatin. On the other hand, TIP60 complex contains two eukaryotic homologs of bacterial RuvB helicase/ATPse, involved in recombination and repair. Accordingly, expression of a dominant negative mutant of TIP60 in living cells interferes with their ability to repair DNA damage, which points out, for the first time, a role for a histone acetyltransferase in a process other than transcription. We also have evidence implicating TIP60 in the apoptotic response to DNA damage.