Transcriptional/epigenetic regulator CBP/p300 in tumorigenesis: structural and functional versatility in target recognition

Abstract

In eukaryotic cells, gene transcription is regulated by sequence-specific DNA-binding transcription factors that recognize promoter and enhancer elements near the transcriptional start site. Some coactivators promote transcription by connecting transcription factors to the basal transcriptional machinery. The highly conserved coactivators CREB-binding protein (CBP) and its paralog, E1A-binding protein (p300), each have four separate transactivation domains (TADs) that interact with the TADs of a number of DNA-binding transcription activators as well as general transcription factors (GTFs), thus mediating recruitment of basal transcription machinery to the promoter. Most promoters comprise multiple activator-binding sites, and many activators contain tandem TADs, thus multivalent interactions may stabilize CBP/p300 at the promoter, and intrinsically disordered regions in CBP/p300 and many activators may confer adaptability to these multivalent complexes. CBP/p300 contains a catalytic histone acetyltransferase (HAT) domain, which remodels chromatin to 'relax' its superstructure and enables transcription of proximal genes. The HAT activity of CBP/p300 also acetylates some transcription factors (e.g., p53), hence modulating the function of key transcriptional regulators. Through these numerous interactions, CBP/p300 has been implicated in complex physiological and pathological processes, and, in response to different signals, can drive cells towards proliferation or apoptosis. Dysregulation of the transcriptional and epigenetic functions of CBP/p300 is associated with leukemia and other types of cancer, thus it has been recognized as a potential anti-cancer drug target. In this review, we focus on recent exciting findings in the structural mechanisms of CBP/p300 involving multivalent and dynamic interactions with binding partners, which may pave new avenues for anti-cancer drug development.

Fig. 1

Functional mechanisms of transcriptional activation by CBP/p300. CBP/p300 promotes transcriptional activity by recruiting transcriptional machinery to the promoter, and by modifying chromatin structure to facilitate transcription. a CBP/p300 functions as a “bridge”, linking the DNA-bound transcription factors (activators) to basal transcription machinery through direct interactions with TFIID (comprised of TATA-binding protein (TBP) and 13 TBP-associated factors (TAFs)), TFIIB, and RNA polymerase II (RNA Pol II), thus promoting pre-initiation complex (PIC) assembly. b CBP/p300 acetylates histones through its histone acetyltransferase (HAT) domain, resulting in chromatin remodeling and relaxation of chromatin structure to enable transcription. CBP/p300 also recruits the coactivators PCAF and GCN5, which also possess HAT activity. c CBP/p300 HAT activity also acetylates certain transcription factors, modulating their activities positively or negatively

Fig. 2

Domain architecture and structures of domains of CBP/p300. The domain architecture of CBP/p300 is shown in the middle with the probability that regions are intrinsically disordered as predicted by DISOPRED2 [217]. The structures of each domain are also shown and labeled. Top the CBP Bromo domain (PDB: 3DWY); the Zn²⁺-binding mode of the PHD domain of CBP/p300 (no high-resolution structure available); the p300 HAT domain in complex with an inhibitor (PDB: 3BIY); the CBP ZZ domain (PDB: 1TOT). Bottom the CBP TAZ1 domain (PDB: 1U2N); KIX domain in complex with FOXO3a CR2C-CR3 (note that KIX comprises two binding sites and the two FOXO3a TADs each bind both sites, thus CR2C-CR3 interacts with KIX in two distinct dynamically exchanging, equally populated orientations. PDB: 2LQH and 2LQI); the p300 TAZ2 domain (PDB: 3IO2); the molten globule state structure of CBP NCBD domain (PDB: 2KKJ), and the structured complex of NCBD with p53 formed through binding-coupled folding (PDB: 2L14). Transactivation domains that primarily interact with transcriptional activators are shown below and those that interact primarily with chromatin are shown on top

Fig. 3

Promiscuous multivalent model of CBP/p300 recruitment. a Many transcription factors contain tandem TADs located in intrinsically disordered regions (IDRs). DNA-binding domains are shown as blue boxes, other structured domains are indicated as cyan boxes, and TADs are labeled and colored purple. Uncoloured regions and most TADs are predicted IDRs, and the percentage of each transcription factor that is comprised of IDRs is indicated. b Multivalent binding model of CBP/p300 recruitment by transcription factors. In the promoter and enhancer regions, there are multiple transcription factor binding sites (TFBSs) for one or more transcription factors. Each TAD interacts weakly with CBP/p300; however, the product of multiple weak binding events would stabilize the interaction, promoting recruitment and initiation of gene transcription. Some transcription factors function as homo- or hetero-dimers, of which each monomer unit may interact with different TADs of CBP/p300 (bottom), recruiting coactivator CBP/p300 more efficiently through multivalent interactions and avoiding competition for one binding site. The IDRs present in CBP/p300 as well as the transcription factors may facilitate recruitment of CBP/p300 in a productive orientation and position, adapting to various chromatin structures

Fig. 4

Compounds that target CBP/p300. Common names of compounds are indicated along with their chemical structures, the CBP/p300 domain targeted, and reported K_d or IC₅₀ values