TRIM37 explained

Tripartite motif-containing protein 37 is an E3 ubiquitin ligase in humans that is encoded by the TRIM37 gene.^{[1] [2] [3] [4]}

Function

This gene encodes a member of the tripartite motif (TRIM) family, whose members are involved in diverse cellular functions such as developmental patterning and oncogenesis. The TRIM motif includes zinc-binding domains, a RING finger region, a B-box motif and a coiled-coil domain. The RING finger and B-box domains chelate zinc and might be involved in protein–protein and/or protein–nucleic acid interactions. The gene mutations are associated with mulibrey (muscle-liver-brain-eye) nanism, an autosomal recessive disorder that involves several tissues of mesodermal origin. Alternatively spliced transcript variants encoding the same protein have been identified. It is responsible for the mono-ubiquitination of histone H2A at lysine 119, a modification commonly associated with transcriptional repression.^[5]

Role in breast cancer

The 17q23 chromosomal region in which the TRIM37 gene is located has been shown to be amplified in up to 40% of breast cancers.^[6] The TRIM37 protein is thought to play a role in breast cancer oncogenesis by ubiquitinating histone H2A in regions occupied by tumor-suppressing genes. This repression of tumor-suppressing genes increases the likelihood that a tumor will occur or that an existing tumor will be more aggressive.

Interactions

TRIM37 has been shown to interact with PRC1.^[7] TRIM37 has also been shown to interact with PRC2 to alter its specificity, and when TRIM37 is overexpressed, there are many changes to gene expression that lead to silencing of tumor-suppressing genes. It has also been shown that TRIM37, PRC2, PRC1 work together to co-bind to target genes, resulting in their transcriptional repression. Knockdown of TRIM37 expression via RNA-interference has shown to result in H2A becoming de-ubiquitinated and the dissociation of PRC1 and PRC2 from target genes. These changes allow the target gene to become transcriptionally active.

See also

• Mulibrey nanism

Further reading

• Nagase T, Ishikawa K, Suyama M, Kikuno R, Hirosawa M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O . 6 . Prediction of the coding sequences of unidentified human genes. XII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro . DNA Research . 5 . 6 . 355–64 . December 1998 . 10048485 . 10.1093/dnares/5.6.355 . free .
• Zapata JM, Pawlowski K, Haas E, Ware CF, Godzik A, Reed JC . A diverse family of proteins containing tumor necrosis factor receptor-associated factor domains . The Journal of Biological Chemistry . 276 . 26 . 24242–52 . June 2001 . 11279055 . 10.1074/jbc.M100354200 . free .
• Reymond A, Meroni G, Fantozzi A, Merla G, Cairo S, Luzi L, Riganelli D, Zanaria E, Messali S, Cainarca S, Guffanti A, Minucci S, Pelicci PG, Ballabio A . 6 . The tripartite motif family identifies cell compartments . The EMBO Journal . 20 . 9 . 2140–51 . May 2001 . 11331580 . 125245 . 10.1093/emboj/20.9.2140 .
• Lehesjoki AE, Reed VA, Mark Gardiner R, Greene ND . Expression of MUL, a gene encoding a novel RBCC family ring-finger protein, in human and mouse embryogenesis . Mechanisms of Development . 108 . 1–2 . 221–5 . October 2001 . 11578880 . 10.1016/S0925-4773(01)00491-9 . 15474684 . free .
• Kallijärvi J, Avela K, Lipsanen-Nyman M, Ulmanen I, Lehesjoki AE . The TRIM37 gene encodes a peroxisomal RING-B-box-coiled-coil protein: classification of mulibrey nanism as a new peroxisomal disorder . American Journal of Human Genetics . 70 . 5 . 1215–28 . May 2002 . 11938494 . 447596 . 10.1086/340256 .
• Jagiello P, Hammans C, Wieczorek S, Arning L, Stefanski A, Strehl H, Epplen JT, Gencik M . 6 . A novel splice site mutation in the TRIM37 gene causes mulibrey nanism in a Turkish family with phenotypic heterogeneity . Human Mutation . 21 . 6 . 630–5 . June 2003 . 12754710 . 10.1002/humu.10220 . 24074182 . free .
• Hämäläinen RH, Avela K, Lambert JA, Kallijärvi J, Eyaid W, Gronau J, Ignaszewski AP, McFadden D, Sorge G, Lipsanen-Nyman M, Lehesjoki AE . 6 . Novel mutations in the TRIM37 gene in Mulibrey Nanism . Human Mutation . 23 . 5 . 522 . May 2004 . 15108285 . 10.1002/humu.9233 . 22994120 . free .
• Kallijärvi J, Lahtinen U, Hämäläinen R, Lipsanen-Nyman M, Palvimo JJ, Lehesjoki AE . TRIM37 defective in mulibrey nanism is a novel RING finger ubiquitin E3 ligase . Experimental Cell Research . 308 . 1 . 146–55 . August 2005 . 15885686 . 10.1016/j.yexcr.2005.04.001 .
• Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . 6 . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–8 . October 2005 . 16189514 . 10.1038/nature04209 . 2005Natur.437.1173R . 4427026 .
• Karlberg N, Jalanko H, Kallijärvi J, Lehesjoki AE, Lipsanen-Nyman M . Insulin resistance syndrome in subjects with mutated RING finger protein TRIM37 . Diabetes . 54 . 12 . 3577–81 . December 2005 . 16306379 . 10.2337/diabetes.54.12.3577 . free .
• Hämäläinen RH, Joensuu T, Kallijärvi J, Lehesjoki AE . Characterisation of the mulibrey nanism-associated TRIM37 gene: transcription initiation, promoter region and alternative splicing . Gene . 366 . 1 . 180–8 . January 2006 . 16310976 . 10.1016/j.gene.2005.08.008 .
• Lim J, Hao T, Shaw C, Patel AJ, Szabó G, Rual JF, Fisk CJ, Li N, Smolyar A, Hill DE, Barabási AL, Vidal M, Zoghbi HY . 6 . A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration . Cell . 125 . 4 . 801–14 . May 2006 . 16713569 . 10.1016/j.cell.2006.03.032 . 13709685 . free .
• Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M . Global, in vivo, and site-specific phosphorylation dynamics in signaling networks . Cell . 127 . 3 . 635–48 . November 2006 . 17081983 . 10.1016/j.cell.2006.09.026 . 7827573 . free .
• Hämäläinen RH, Mowat D, Gabbett MT, O'brien TA, Kallijärvi J, Lehesjoki AE . Wilms' tumor and novel TRIM37 mutations in an Australian patient with mulibrey nanism . Clinical Genetics . 70 . 6 . 473–9 . December 2006 . 17100991 . 10.1111/j.1399-0004.2006.00700.x . 20007234 .
• Doğanc T, Yüksel Konuk BE, Alpan N, Konuk O, Hämäläinen RH, Lehesjoki AE, Tekin M . A novel mutation in TRIM37 is associated with mulibrey nanism in a Turkish boy . Clinical Dysmorphology . 16 . 3 . 173–6 . July 2007 . 17551331 . 10.1097/MCD.0b013e3280f6d00b . 45965305 .

Notes and References

1. Avela K, Lipsanen-Nyman M, Perheentupa J, Wallgren-Pettersson C, Marchand S, Fauré S, Sistonen P, de la Chapelle A, Lehesjoki AE . 6 . Assignment of the mulibrey nanism gene to 17q by linkage and linkage-disequilibrium analysis . American Journal of Human Genetics . 60 . 4 . 896–902 . April 1997 . 9106536 . 1712467 .
2. Avela K, Lipsanen-Nyman M, Idänheimo N, Seemanová E, Rosengren S, Mäkelä TP, Perheentupa J, Chapelle AD, Lehesjoki AE . 6 . Gene encoding a new RING-B-box-Coiled-coil protein is mutated in mulibrey nanism . Nature Genetics . 25 . 3 . 298–301 . July 2000 . 10888877 . 10.1038/77053 . 24257747 .
3. Web site: Entrez Gene: TRIM37 tripartite motif-containing 37.
4. Bhatnagar S, Gazin C, Chamberlain L, Ou J, Zhu X, Tushir JS, Virbasius CM, Lin L, Zhu LJ, Wajapeyee N, Green MR . 6 . TRIM37 is a new histone H2A ubiquitin ligase and breast cancer oncoprotein . Nature . 516 . 7529 . 116–20 . December 2014 . 25470042 . 4269325 . 10.1038/nature13955 . 2014Natur.516..116B .
5. Weake VM, Workman JL . Histone ubiquitination: triggering gene activity . en . Molecular Cell . 29 . 6 . 653–63 . March 2008 . 18374642 . 10.1016/j.molcel.2008.02.014 . free .
6. Sinclair. Colleen S.. Rowley. Matthew. Naderi. Ali. Couch. Fergus J.. 2003-04-01. The 17q23 Amplicon and Breast Cancer. Breast Cancer Research and Treatment. en. 78. 3. 313–322. 10.1023/A:1023081624133. 12755490. 23751525. 1573-7217.
7. Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . 6 . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–8 . October 2005 . 16189514 . 10.1038/nature04209 . Huda Zoghbi . 2005Natur.437.1173R . 4427026 .