Abstract
KAP1 is a nuclear corepressor with conserved domains for RING finger, B boxes, leucine zipper alpha helical coiled-coil region, plant homeo domain finger, and bromo domain. The plant homeo domain finger and bromo domain of KAP1 cooperatively function as a transcription repression domain by recruiting the histone deacetylase complex NuRD and histone H3 lysine 9-specific methyltransferase SETDB1. Here we report that KAP1 binds the E2F1 transcription factor in a retinoblastoma protein (pRb)-independent fashion and inhibits E2F1 activity. KAP1 stimulates formation of E2F1-HDAC1 complex and inhibits E2F1 acetylation. Ectopic expression of KAP1 represses E2F1 transcription and apoptosis functions independent of pRb. Depletion of endogenous KAP1 in pRb-deficient Saos2 cells by RNA interference increases E2F1 acetylation level, stimulates E2F1 transcriptional activity, and sensitizes apoptosis response to DNA damage. Therefore, KAP1 contributes to the negative regulation of E2F1 and may serve as a partial backup to prevent E2F1-mediated apoptosis in the absence of pRb.
Highlights
The retinoblastoma protein pRb3 has been established as the principle regulator of E2F1 [10]. pRb forms a complex with
KAP1 Forms a Complex with E2F1 and Regulates E2F1 Activity—E2F1 is regulated by interaction with the retinoblastoma protein pRb, which recruits histone deacetylase and methylase to suppress E2F1 target promoters
The results presented above showed that the nuclear corepressor protein KAP1 is involved in the regulation of E2F1 in a pRb-independent fashion
Summary
The retinoblastoma protein pRb3 has been established as the principle regulator of E2F1 [10]. pRb forms a complex with. It is clear that E2F1 activity is controlled by multiple factors in addition to pRb. The TopBP1 protein has been shown to bind E2F1 independent of pRb and recruits Brg, a central component of the SWI/SNF chromatin-remodeling complex to repress E2F1 target promoters [12, 13]. The C-terminal plant homeo domain finger and bromo domain of KAP1 cooperatively function as a transcription repression domain by recruiting the histone deacetylase complex NuRD and histone H3 lysine 9-specific methyltransferase SETDB1 [18, 19]. KAP1 may function as a corepressor in part by being targeted to DNA by other transcription factors and promotes modification of chromatin structure. KAP1 depletion by RNA interference increases p53 activity after DNA damage, which may contribute to increased apoptosis
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