EP400 (E1A binding protein p400)

2007-06-01 Sandrine Tyteca Affiliation

Chromatin, Cell Proliferation group, LBCMCP-UMR 5088 CNRS, Universite Paul Sabatier, Bat 4R3B1, 118 route de Narbonne, 31062 Toulouse Cedex 9, France

Identity

HGNC

EP400

LOCATION

12q24.33

LOCUSID

57634

ALIAS

CAGH32,P400,TNRC12

FUSION GENES

Show Gene Fusions

DNA/RNA

Description

The EP400 gene consists of 52 exons and spans 130.5 kb of genomic sequence on chromosome 12.

Transcription

The predominant mRNA transcribed from this gene is 12,265 nt long. This is actually the isoform 2 of EP400.
Three other isoforms generated by alternative splicing have been described :

Isoform 1 retains an alternatively spliced sequence inside intron 2.

Isoform 3 lacks exon 4.

Isoform 4 lacks exon 23.

Pseudogene

There is an EP400 pseudogene termed "EP400 N-terminal like" (EP400-NL) in the same locus.

Proteins

Description

The EP400 protein (isoform 2) is 3124 amino acids long and its molecular weight is about 400 kDa. It was cloned and characterized in 2001 thanks to its interation with the E1A oncoprotein.

Isoform 1 produces a 3160 aa long protein.

Isoform 3 produces a 3087 aa long protein.

Isoform 4 produces a 3043 aa long protein.
There has been no experimental confirmation for isoforms 3 and 4.
The only described post-translational modification is a phosphorylation on Ser736.

Expression

No data.

Localisation

EP400 belongs to chromatin remodelling complexes which are located in the nucleus, so it is probably nuclear. However, its cellular localization has not been formally monitored to date.

Function

EP400 belongs to the SWI2/SNF2 family of ATPases and is found in two highly related chromatin remodelling complexes : the Tip60 and p400 complexes. In these complexes, EP400 is associated with other enzymes such as the Tip60 histone acetyltransferase and/or the RuvBL1 and RuvBL2 helicases. (Note : putative specific functions of each splicing variant have not been investigated to date)

Functions at the cellular level :
EP400 has been implicated in cell cycle control, apoptosis and development.
First, the depletion of EP400 in untransformed human fibroblasts leads to senescence through induction of the p53-p21 pathway. Likewise, the EP400 knock-down induces a p21-dependent cell cycle arrest in human cell lines. According to these results, EP400 seems to favour cell proliferation.
On the other hand, EP400 is required for E1A-mediated apoptosis. Similarly, EP400 is required for apoptosis upon DNA damage in human cell lines. Thus, EP400 also favours apoptosis, possibly through preventing cell cycle arrest.
Finally, the murine homolog of EP400 appears to be involved in embryonic hematopoiesis.

Functions at the molecular level :
EP400 has ATP-dependent chromatin remodelling activity. Accordingly, EP400 was shown to be recruited along with the Tip60 complex on promoters by the c-myc and E2F transcription factors. Moreover, the EP400 homolog in drosophila is able to exchange specific histone variants at double-strand breaks.

Homology

EP400 contains the SNF2 N-terminal domain shared by all ATPases of the SWI2/SNF2 family (SNF2, STH1, RAD16, RAD54, ISWI...). It also bears helicase-specific domains (see diagram):

an helicase C-terminal domain

an HSA domain

a DEXH box which contains the ATP-binding region.

Putative homologs in other species (non exhaustive) :

M.musculus : Ep400

R.norvegicus : Ep400

G.gallus : EP400

D.melanogaster : DOM or domino

Implicated in

Entity name

Cancers

Oncogenesis

It was shown that EP400 is a target for the E1A viral oncoprotein transforming activity.
Indeed, studies showed that the overexpression of specific EP400 fragments corresponding to the E1A binding region (the SWI2/SNF2 domain) enhance the ability of E1A to transform rat embryo fibroblasts in the presence of ras. Moreover, the same fragments are able to partially restore the transforming activity of a tranformation-defective E1A mutant.

Bibliography

Pubmed ID	Last Year	Title	Authors
15302935	2004	Large-scale characterization of HeLa cell nuclear phosphoproteins.	Beausoleil SA et al
15655109	2005	The p400 E1A-associated protein is a novel component of the p53 --> p21 senescence pathway.	Chan HM et al
17486071	2007	p400 function is required for the adenovirus E1A-mediated suppression of EGFR and tumour cell killing.	Flinterman MB et al
12776177	2003	MYC recruits the TIP60 histone acetyltransferase complex to chromatin.	Frank SR et al
11509179	2001	The p400 complex is an essential E1A transformation target.	Fuchs M et al
15528408	2004	Acetylation by Tip60 is required for selective histone variant exchange at DNA lesions.	Kusch T et al
15741165	2005	p400 is required for E1A to promote apoptosis.	Samuelson AV et al
16601686	2006	Tip60 and p400 are both required for UV-induced apoptosis but play antagonistic roles in cell cycle progression.	Tyteca S et al
17535249	2007	Critical role of the p400/mDomino chromatin-remodeling ATPase in embryonic hematopoiesis.	Ueda T et al

Other Information

Locus ID:

NCBI: 57634
MIM: 606265
HGNC: 11958
Ensembl: ENSG00000183495

Variants:

dbSNP: 57634
ClinVar: 57634
TCGA: ENSG00000183495
COSMIC: EP400

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000183495	ENST00000330386	A0A0A0MR70
ENSG00000183495	ENST00000332482	A0A0A0MR72
ENSG00000183495	ENST00000333577	A0A0A0MR80
ENSG00000183495	ENST00000389561	Q96L91

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Cellular responses to stress	REACTOME	R-HSA-2262752
Cellular Senescence	REACTOME	R-HSA-2559583
DNA Damage/Telomere Stress Induced Senescence	REACTOME	R-HSA-2559586
Formation of Senescence-Associated Heterochromatin Foci (SAHF)	REACTOME	R-HSA-2559584
Chromatin organization	REACTOME	R-HSA-4839726
Chromatin modifying enzymes	REACTOME	R-HSA-3247509
HATs acetylate histones	REACTOME	R-HSA-3214847

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
20876283	2010	The p400 ATPase regulates nucleosome stability and chromatin ubiquitination during DNA repair.	90
18985155	2008	Analysis of Myc-induced histone modifications on target chromatin.	58
15655109	2005	The p400 E1A-associated protein is a novel component of the p53 --> p21 senescence pathway.	54
19169279	2009	The p400/Tip60 ratio is critical for colorectal cancer cell proliferation through DNA damage response pathways.	38
16601686	2006	Tip60 and p400 are both required for UV-induced apoptosis but play antagonistic roles in cell cycle progression.	37
23266955	2012	The chromatin remodeler p400 ATPase facilitates Rad51-mediated repair of DNA double-strand breaks.	31
26669263	2016	EP400 Deposits H3.3 into Promoters and Enhancers during Gene Activation.	24
15741165	2005	p400 is required for E1A to promote apoptosis.	22
20351180	2010	The SANT domain of p400 ATPase represses acetyltransferase activity and coactivator function of TIP60 in basal p21 gene expression.	20
24332572	2014	A blood-based three-gene signature for the non-invasive detection of early human hepatocellular carcinoma.	20

Citation

Sandrine Tyteca

EP400 (E1A binding protein p400)

Atlas Genet Cytogenet Oncol Haematol. 2007-06-01

Online version: http://atlasgeneticsoncology.org/gene/40457/ep400-(e1a-binding-protein-p400)