Transformation/transcription domain-associated protein

Transformation/transcription domain-associated protein
Identifiers
Symbols	TRRAP ; PAF350/400; PAF400; STAF40; TR-AP; Tra1
External IDs	OMIM: 603015 MGI: 2153272 HomoloGene: 39246 GeneCards: TRRAP Gene
Gene ontology Molecular function • transcription cofactor activity • transcription coactivator activity • protein binding • kinase activity • phosphotransferase activity, alcohol group as acceptor Cellular component • PCAF complex • Swr1 complex • nucleus • nucleoplasm • Golgi apparatus • STAGA complex • transcription factor TFTC complex • NuA4 histone acetyltransferase complex Biological process • DNA repair • chromatin organization • transcription, DNA-templated • regulation of transcription, DNA-templated • mitotic cell cycle checkpoint • phosphorylation • histone acetylation • histone deubiquitination • histone H4 acetylation • histone H2A acetylation Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	8295	100683
Ensembl	ENSG00000196367	ENSMUSG00000045482
UniProt	Q9Y4A5	Q80YV3
RefSeq (mRNA)	NM_001244580	NM_001081362
RefSeq (protein)	NP_001231509	NP_001074831
Location (UCSC)	Chr 7: 98.88 – 99.01 Mb	Chr 5: 144.77 – 144.86 Mb
PubMed search

Transformation/transcription domain-associated protein, also known asTRRAP, is a protein that in humans is encoded by the TRRAP gene.^[1][2] TRRAP belongs to the phosphatidylinositol 3-kinase-related kinase protein family.

Function

TRRAP is an adapter protein, which is found in various multiprotein chromatin complexes with histone acetyltransferase activity (HAT), which in turn is responsible for epigenetic transcription activation. TRRAP has a central role in MYC (c-Myc) transcription activation, and also participates in cell transformation by MYC. It is required for p53/TP53-, E2F1-, and E2F4-mediated transcription activation. It is also involved in transcription activation mediated by the adenovirus E1A, a viral oncoprotein that deregulates transcription of key genes.^[3]

TRRAP is also required for the mitotic checkpoint and normal cell cycle progression. The MRN complex (composed of MRE11, RAD50, and NBS1) is involved in the detection and repair of DNA double-strand breaks (DSBs). TRRAP associates with the MRN complex and when TRRAP is removed, the complex shows reduced cDNA end-joining activity. Hence, TRRAP may function as a link between DSB repair and chromatin remodeling.^[4][5]

Model organisms

Trrap knockout mouse phenotype

Characteristic	Phenotype
Homozygote viability	Abnormal
Recessive lethal study	Abnormal
Body weight	Normal
Anxiety	Normal
Neurological assessment	Normal
Grip strength	Normal
Hot plate	Normal
Dysmorphology	Normal
Indirect calorimetry	Normal
Glucose tolerance test	Normal
Auditory brainstem response	Normal
DEXA	Normal
Radiography	Normal
Body temperature	Normal
Eye morphology	Normal
Clinical chemistry	Normal
Plasma immunoglobulins	Normal
Haematology	Normal[6]
Peripheral blood lymphocytes	Normal
Micronucleus test	Normal
Heart weight	Normal
Brain histopathology	Normal
Salmonella infection	Normal[7]
Citrobacter infection	Normal[8]
All tests and analysis from[9][10]

Model organisms have been used in the study of TRRAP function. A conditional knockout mouse line, called Trrap^{tm1a(EUCOMM)Wtsi[11][12]} was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.^[13][14][15]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.^[9][16] Twenty four tests were carried out on mutant mice and two significant abnormalities were observed.^[9] No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no significant abnormalities were observed in these animals.^[9]

Interactions

Transformation/transcription domain-associated protein has been shown to interact with:

• ACTL6A,^[17]
• EP400,^[18]
• MAX,^[1][19]
• Myc,^{[1][17][19][20]}
• PCAF,^[18][20]
• SUPT3H,^[21] and
• TAF9.^[21] and

References

1. McMahon SB, Van Buskirk HA, Dugan KA, Copeland TD, Cole MD (August 1998). "The novel ATM-related protein TRRAP is an essential cofactor for the c-Myc and E2F oncoproteins". Cell 94 (3): 363–74. doi:10.1016/S0092-8674(00)81479-8. PMID 9708738.
2. Vassilev A, Yamauchi J, Kotani T, Prives C, Avantaggiati ML, Qin J, Nakatani Y (December 1998). "The 400 kDa subunit of the PCAF histone acetylase complex belongs to the ATM superfamily". Mol. Cell 2 (6): 869–75. doi:10.1016/S1097-2765(00)80301-9. PMID 9885574.
3. Murr R, Vaissière T, Sawan C, Shukla V, Herceg Z (August 2007). "Orchestration of chromatin-based processes: mind the TRRAP". Oncogene 26 (37): 5358–72. doi:10.1038/sj.onc.1210605. PMID 17694078.
4. Robert F, Hardy S, Nagy Z, Baldeyron C, Murr R, Déry U, Masson JY, Papadopoulo D, Herceg Z, Tora L (January 2006). "The Transcriptional Histone Acetyltransferase Cofactor TRRAP Associates with the MRN Repair Complex and Plays a Role in DNA Double-Strand Break Repair". Mol. Cell. Biol. 26 (2): 402–12. doi:10.1128/MCB.26.2.402-412.2006. PMC 1346889. PMID 16382133.
5. Herceg Z, Wang ZQ (March 2005). "Rendez-vous at mitosis: TRRAPed in the chromatin". Cell Cycle 4 (3): 383–7. doi:10.4161/cc.4.3.1546. PMID 15711126.
6. "Haematology data for Trrap". Wellcome Trust Sanger Institute.
7. "Salmonella infection data for Trrap". Wellcome Trust Sanger Institute.
8. "Citrobacter infection data for Trrap". Wellcome Trust Sanger Institute.
9. Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x.
10. Mouse Resources Portal, Wellcome Trust Sanger Institute.
11. "International Knockout Mouse Consortium".
12. "Mouse Genome Informatics".
13. Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature 474 (7351): 337–342. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
14. Dolgin E (2011). "Mouse library set to be knockout". Nature 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
15. Collins FS, Rossant J, Wurst W (2007). "A Mouse for All Reasons". Cell 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
16. van der Weyden L, White JK, Adams DJ, Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism.". Genome Biol 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837. PMID 21722353.
17. Park J, Wood MA, Cole MD (March 2002). "BAF53 forms distinct nuclear complexes and functions as a critical c-Myc-interacting nuclear cofactor for oncogenic transformation". Mol. Cell. Biol. 22 (5): 1307–16. doi:10.1128/mcb.22.5.1307-1316.2002. PMC 134713. PMID 11839798.
18. Fuchs M, Gerber J, Drapkin R, Sif S, Ikura T, Ogryzko V, Lane WS, Nakatani Y, Livingston DM (August 2001). "The p400 complex is an essential E1A transformation target". Cell 106 (3): 297–307. doi:10.1016/s0092-8674(01)00450-0. PMID 11509179.
19. McMahon SB, Wood MA, Cole MD (January 2000). "The essential cofactor TRRAP recruits the histone acetyltransferase hGCN5 to c-Myc". Mol. Cell. Biol. 20 (2): 556–62. doi:10.1128/mcb.20.2.556-562.2000. PMC 85131. PMID 10611234.
20. Liu X, Tesfai J, Evrard YA, Dent SY, Martinez E (May 2003). "c-Myc transformation domain recruits the human STAGA complex and requires TRRAP and GCN5 acetylase activity for transcription activation". J. Biol. Chem. 278 (22): 20405–12. doi:10.1074/jbc.M211795200. PMC 4031917. PMID 12660246.
21. Martinez E, Palhan VB, Tjernberg A, Lymar ES, Gamper AM, Kundu TK, Chait BT, Roeder RG (October 2001). "Human STAGA complex is a chromatin-acetylating transcription coactivator that interacts with pre-mRNA splicing and DNA damage-binding factors in vivo". Mol. Cell. Biol. 21 (20): 6782–95. doi:10.1128/MCB.21.20.6782-6795.2001. PMC 99856. PMID 11564863.

Further reading

• Herceg Z, Wang ZQ (2006). "Rendez-vous at mitosis: TRRAPed in the chromatin". Cell Cycle 4 (3): 383–7. doi:10.4161/cc.4.3.1546. PMID 15711126.
• Murr R, Vaissière T, Sawan C, Shukla V, Herceg Z (2007). "Orchestration of chromatin-based processes: mind the TRRAP". Oncogene 26 (37): 5358–72. doi:10.1038/sj.onc.1210605. PMID 17694078.
• McMahon SB, Van Buskirk HA, Dugan KA, Copeland TD, Cole MD (1998). "The novel ATM-related protein TRRAP is an essential cofactor for the c-Myc and E2F oncoproteins". Cell 94 (3): 363–74. doi:10.1016/S0092-8674(00)81479-8. PMID 9708738.
• Vassilev A, Yamauchi J, Kotani T, Prives C, Avantaggiati ML, Qin J, Nakatani Y (1999). "The 400 kDa subunit of the PCAF histone acetylase complex belongs to the ATM superfamily". Mol. Cell 2 (6): 869–75. doi:10.1016/S1097-2765(00)80301-9. PMID 9885574.
• Brand M, Yamamoto K, Staub A, Tora L (1999). "Identification of TATA-binding protein-free TAFII-containing complex subunits suggests a role in nucleosome acetylation and signal transduction". J. Biol. Chem. 274 (26): 18285–9. doi:10.1074/jbc.274.26.18285. PMID 10373431.
• McMahon SB, Wood MA, Cole MD (2000). "The Essential Cofactor TRRAP Recruits the Histone Acetyltransferase hGCN5 to c-Myc". Mol. Cell. Biol. 20 (2): 556–62. doi:10.1128/MCB.20.2.556-562.2000. PMC 85131. PMID 10611234.
• Ikura T, Ogryzko VV, Grigoriev M, Groisman R, Wang J, Horikoshi M, Scully R, Qin J, Nakatani Y (2000). "Involvement of the TIP60 histone acetylase complex in DNA repair and apoptosis". Cell 102 (4): 463–73. doi:10.1016/S0092-8674(00)00051-9. PMID 10966108.
• Brand M, Moggs JG, Oulad-Abdelghani M, Lejeune F, Dilworth FJ, Stevenin J, Almouzni G, Tora L (2001). "UV-damaged DNA-binding protein in the TFTC complex links DNA damage recognition to nucleosome acetylation". EMBO J. 20 (12): 3187–96. doi:10.1093/emboj/20.12.3187. PMC 150203. PMID 11406595.
• Lee YJ, Chung TS, Yoon YS, Lee MS, Han SH, Seong GJ, Ahn KJ (2001). "The role of functional MR imaging in patients with ischemia in the visual cortex". AJNR. American journal of neuroradiology 22 (6): 1043–9. PMID 11415895.
• Lang SE, McMahon SB, Cole MD, Hearing P (2001). "E2F transcriptional activation requires TRRAP and GCN5 cofactors". J. Biol. Chem. 276 (35): 32627–34. doi:10.1074/jbc.M102067200. PMID 11418595.
• Park J, Kunjibettu S, McMahon SB, Cole MD (2001). "The ATM-related domain of TRRAP is required for histone acetyltransferase recruitment and Myc-dependent oncogenesis". Genes Dev. 15 (13): 1619–24. doi:10.1101/gad.900101. PMC 312730. PMID 11445536.
• Fuchs M, Gerber J, Drapkin R, Sif S, Ikura T, Ogryzko V, Lane WS, Nakatani Y, Livingston DM (2001). "The p400 complex is an essential E1A transformation target". Cell 106 (3): 297–307. doi:10.1016/S0092-8674(01)00450-0. PMID 11509179.
• Martinez E, Palhan VB, Tjernberg A, Lymar ES, Gamper AM, Kundu TK, Chait BT, Roeder RG (2001). "Human STAGA Complex Is a Chromatin-Acetylating Transcription Coactivator That Interacts with Pre-mRNA Splicing and DNA Damage-Binding Factors In Vivo". Mol. Cell. Biol. 21 (20): 6782–95. doi:10.1128/MCB.21.20.6782-6795.2001. PMC 99856. PMID 11564863.
• Park J, Wood MA, Cole MD (2002). "BAF53 Forms Distinct Nuclear Complexes and Functions as a Critical c-Myc-Interacting Nuclear Cofactor for Oncogenic Transformation". Mol. Cell. Biol. 22 (5): 1307–16. doi:10.1128/MCB.22.5.1307-1316.2002. PMC 134713. PMID 11839798.
• Yanagisawa J, Kitagawa H, Yanagida M, Wada O, Ogawa S, Nakagomi M, Oishi H, Yamamoto Y, Nagasawa H, McMahon SB, Cole MD, Tora L, Takahashi N, Kato S (2002). "Nuclear receptor function requires a TFTC-type histone acetyl transferase complex". Mol. Cell 9 (3): 553–62. doi:10.1016/S1097-2765(02)00478-1. PMID 11931763.
• Nikiforov MA, Chandriani S, Park J, Kotenko I, Matheos D, Johnsson A, McMahon SB, Cole MD (2002). "TRRAP-Dependent and TRRAP-Independent Transcriptional Activation by Myc Family Oncoproteins". Mol. Cell. Biol. 22 (14): 5054–63. doi:10.1128/MCB.22.14.5054-5063.2002. PMC 139788. PMID 12077335.
• Ard PG, Chatterjee C, Kunjibettu S, Adside LR, Gralinski LE, McMahon SB (2002). "Transcriptional Regulation of the mdm2 Oncogene by p53 Requires TRRAP Acetyltransferase Complexes". Mol. Cell. Biol. 22 (16): 5650–61. doi:10.1128/MCB.22.16.5650-5661.2002. PMC 133988. PMID 12138177.
• Cavusoglu N, Brand M, Tora L, Van Dorsselaer A (2003). "Novel subunits of the TATA binding protein free TAFII-containing transcription complex identified by matrix-assisted laser desorption/ionization-time of flight mass spectrometry following one-dimensional gel electrophoresis". Proteomics 3 (2): 217–23. doi:10.1002/pmic.200390030. PMID 12601814.
• Liu X, Tesfai J, Evrard YA, Dent SY, Martinez E (2003). "c-Myc transformation domain recruits the human STAGA complex and requires TRRAP and GCN5 acetylase activity for transcription activation". J. Biol. Chem. 278 (22): 20405–12. doi:10.1074/jbc.M211795200. PMC 4031917. PMID 12660246.