Gene Section Mini Review

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(2) 103

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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CREBBP (CREB binding protein) Cristina Gervasini

Division of Medical Genetics, San Paolo School of Medicine, University of Milan, 20142 Milan, Italy (CG)

Published in Atlas Database: March 2009

Online updated version: http://AtlasGeneticsOncology.org/Genes/CBPID42.html DOI: 10.4267/2042/44677

This article is an update of: Huret JL. CBP (CREB-binding protein). Atlas Genet Cytogenet Oncol Haematol 2000;4(3):101-102 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Other names: CBP (cAMP Response Element-Binding Protein (CREB)-binding protein); RSTS (Rubinstein-Taybi syndrome); KAT3A

HGNC (Hugo): CREBBP

Location: 16p13.3

Local order: centromere-ADCY9-CREBBP-TRAP1-telomere.

A: CBP (16p22) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. Laboratories willing to validate the probes are welcome : contact rocchi@biologia.uniba.it. B: Map showing the position of BAC clone RP11-1072J2 (UCSC Genome Browser assembly Mar 2006), centered on CREBBP gene (top) and two images of partial metaphases from normal controls showing, after FISH, CREBBP-specific signals at 16p13.3 (bottom).

DNA/RNA Description The gene spans about 155 kb; transcription from centromere to telomere, number of exons: 31.

Transcription 10 kb mRNA, with a 7.3 kb coding sequence, start codon in exon 1, stop codon in exon 31.

Protein Description 2442 amino acids; 265351 Da; predict PI=8.83; Known domains are: KIX= CREB binding, Bromo= Bromodomain, Zn=zinc-finger (corresponding to cysteine-histidine rich regions), HAT= acetyl transferasic, Q= poly Glutaminic stretch. From the carboxy to the N-terminus: Q-Zn-HAT-Zn-Bromo-KIX-Zn. Reported isoform b (2402 aa) lacking aa406-444 (exon 5). Methylation of the KIX domain by CARM1 blocks association with CREB. Phosphorylated upon DNA damage, probably by ATM or ATR.

Expression Wide expression; expression in the whole embryo as well brain; cDNA sources: mammary gland; lung; placenta; testis; lymph node; thymus; mouth; ear; kidney; embryonic tissue; larynx; pancreas; intestine; blood; heart; amniotic fluid; trachea; liver; thyroid; skin; connective tissue; uterus; eye; prostate; stomach; ovary; salivary gland; muscle; adrenal gland; bone marrow; adipose tissue; spleen; nerve; bone; bladder.

CREBBP (CREB binding protein) Gervasini C

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(2) 104

Localisation Nucleus.

Function Binds specifically to phosphorylate CREB and enhances its transcriptional activity toward cAMP-responsive genes; Acts as transcription co-activator by: i) enabling the interaction between different TF and RNAPolII complexes, ii) serving as molecular scaffold that brings enzymes to the promoter, iii) remodelling the chromatin favouring the open status, by histone and non-histone proteins acetylation. Essential role in embryogenesis, cell differentiation, apoptosis, and proliferation; Involved in the regulation of cell cycle during G1/S transition.

Homology EP300

Implicated in t(8;16)(p11;p13)/M4 ANLL --> MOZ/CBP Disease Acute non lymphocytic leukemia (ANLL) and treatment related ANLL (t-ANLL).

Prognosis Poor: remission is obtained in half cases; survival is often less than 1yr.

Cytogenetics +8 as an additional anomalies in half cases.

Hybrid/Mutated gene 5' MOZ - 3' CBP.

Abnormal protein N-term finger motifs and acetyl transferase from MOZ fused to most of CBP, with a breakpoint in 5' of the CREB binding domain of CBP.

Top: Ideogram of chromosome 16 and chromosomal localisation of the CREBBP gene. Middle: the genomic region including CREBBP (red) and flanking genes is zoomed. Deletions spanning CREBBP and adjacent sequences (accounting for about 10% of CREBBP mutations) are indicated by black lines. Mosaic deletions (only 3 so far detected) are asterisked; dotted lines target low-resolution mapped breakpoints. So far 22 deletions have been reported and the differently sized ones (21) are here diagrammed. Bottom: structure of CREBBP gene and protein. Different colours are used to link gene exons (pictured by rectangles) and corresponding protein domains. Different reported point mutations (n.108 in Leiden Open Variation Database) are shown: filled circles (nonsense) and dotted circles (frameshift), squares (missense) and triangles (splicing). Most mutations cluster to exons encoding the HAT domain. Known domains from the carbossi-terminal are: Q= poly Glutaminic stretch, Zn=zinc-finger, HAT= acetyl transferasic, Bromo= Bromodomain, KIX= CREB binding).

CREBBP (CREB binding protein) Gervasini C

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(2) 105

t(10;16)(q22;p13)/M4 ANLL --> MYST4/CBP Disease Acute myeloid leukaemia (AML) M4/M5a and therapy-related myelodysplastic syndromes (MDS). Only 4 cases described.

Prognosis Poor, bad response to chemotherapy.

Hybrid/Mutated gene 5' MYST4 - 3' CBP.

Abnormal protein In-frame fusion between MYST4 exon 17 and CREBBP exon 3. Variants fusing MYST4 exon 16 and CREBBP exon 5; MYST4 exon 17 and CREBBP exon 7 have been also described. CREBBP-MYST4 transcripts have been detected.

t(11;16)(q23;p13)/t-ANLL --> MLL/CBP Disease Therapy related ANLL (t-ANLL); should be very close to the t(11;22)(q23;q13).

Prognosis Likely to be poor.

Hybrid/Mutated gene 5' MLL - 3'CBP.

Abnormal protein N-term AT hook and DNA methyltransferase from MLL fused to most of CBP; variable brakpoint in CBP: either 5' to the CREB binding domain (like in the t(8;16)), or just upstream the bromodomain.

Rubinstein-Taybi syndrome Note Due to CBP haploinsufficiency.

Disease Rare autosomal dominant congenital disorder characterized by postnatal growth retardation and psychomotor developmental delay, skeletal anomalies (broad and duplicated distal phalanges of thumbs and halluces are a landmark sign) and specific facial dysmorphisms. The latter include down-slanted palpebral fissures, broad nasal bridge, beaked nose and micrognathia. In addition, patients with RSTS have an increased, although not well documented, risk of tumor formation.

Breakpoints

CREBBP (CREB binding protein) Gervasini C

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Localization of breakpoints affecting CREBBP and partner genes in leukaemia-associated balanced translocations.

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CREBBP (CREB binding protein) Gervasini C

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This article should be referenced as such:

Gervasini C. CREBBP (CREB binding protein). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(2):103-107.