CREBBP

Chr 16AD

CREB binding protein

NCBI Gene: 1387 ENSG00000005339 UniProt: Q92793 OMIM: 600140

The protein functions as a transcriptional coactivator with histone acetyltransferase activity that couples chromatin remodeling to transcription factor recognition, playing critical roles in embryonic development, growth control, and homeostasis. Mutations cause Rubinstein-Taybi syndrome 1 and Menke-Hennekam syndrome 1, inherited in an autosomal dominant pattern, predominantly through loss-of-function mechanisms leading to haploinsufficiency. The gene shows extreme intolerance to loss-of-function variants (pLI = 1, LOEUF = 0.066), consistent with the pathogenic effects of reduced dosage.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Acetylates histones, giving a specific tag for transcriptional activation (PubMed:21131905, PubMed:24616510). Mediates acetylation of histone H3 at 'Lys-18' and 'Lys-27' (H3K18ac and H3K27ac, respectively) (PubMed:21131905). Also acetylates non-histone proteins, like DDX21, FBL, IRF2, MAFG, NCOA3, POLR1E/PAF53 and FOXO1 (PubMed:10490106, PubMed:11154691, PubMed:12738767, PubMed:12929931, PubMed:24207024, PubMed:28790157, PubMed:30540930, PubMed:35675826, PubMed:9707565). Binds specifically to phosphorylated CREB and enhances its transcriptional activity toward cAMP-responsive genes. Acts as a coactivator of ALX1. Acts as a circadian transcriptional coactivator which enhances the activity of the circadian transcriptional activators: NPAS2-BMAL1 and CLOCK-BMAL1 heterodimers (PubMed:14645221). Acetylates PCNA; acetylation promotes removal of chromatin-bound PCNA and its degradation during nucleotide excision repair (NER) (PubMed:24939902). Acetylates POLR1E/PAF53, leading to decreased association of RNA polymerase I with the rDNA promoter region and coding region (PubMed:24207024). Acetylates DDX21, thereby inhibiting DDX21 helicase activity (PubMed:28790157). Acetylates FBL, preventing methylation of 'Gln-105' of histone H2A (H2AQ104me) (PubMed:30540930). In addition to protein acetyltransferase, can use different acyl-CoA substrates, such as lactoyl-CoA, and is able to mediate protein lactylation (PubMed:38128537). Catalyzes lactylation of MRE11 in response to DNA damage, thereby promoting DNA double-strand breaks (DSBs) via homologous recombination (HR) (PubMed:38128537). Functions as a transcriptional coactivator for SMAD4 in the TGF-beta signaling pathway (PubMed:25514493)

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Menke-Hennekam syndrome 1MIM #618332

Rubinstein-Taybi syndrome 1MIM #180849

Clinical highlights

Gene-disease validity (ClinGen)

Rubinstein-Taybi syndrome · ADDefinitivesufficient evidence for diagnostic panels

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

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Pubs (1 yr)

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P/LP submissions

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P/LP missense

0.07

LOEUF· LoF intol.

LOF

Mechanism· G2P