TRIP13

TRIP13 is a mammalian gene that encodes the thyroid receptor-interacting protein 13. In budding yeast, the analog for TRIP13 is PCH2. TRIP13 is a member of the AAA+ ATPase family, a family known for mechanical forces derived from ATP hydrolase reactions. The TRIP13 gene has been shown to interact with a variety of proteins and implicated in a few diseases, notably interacting with the ligand binding domain of thyroid hormone receptors, and may play a role in early-stage non-small cell lung cancer.[4] However, recent evidence implicates TRIP13 in various cell cycle phases, including meiosis G2/Prophase and during the Spindle Assembly checkpoint (SAC). Evidence shows regulation to occur through the HORMA domains, including Hop1, Rev7, and Mad2.[5] Of note, Mad2's involvement in the SAC is shown to be affected by TRIP13 [6] Due to TRIP13's role in cell cycle arrest and progression, it may present opportunity as a therapeutic candidate for cancers.[7]

TRIP13
Identifiers
Aliases	TRIP13, 16E1BP, thyroid hormone receptor interactor 13, MVA3
External IDs	OMIM: 604507 MGI: 1916966 HomoloGene: 3125 GeneCards: TRIP13
Gene location (Human) Chr. Chromosome 5 (human)[1] Band 5p15.33 Start 892,884 bp[1] End 919,357 bp[1]
RNA expression pattern More reference expression data
Gene ontology Molecular function • nucleotide binding • GO:0001948 protein binding • GO:0001104 transcription cofactor activity • ATP binding • identical protein binding Cellular component • male germ cell nucleus • cell nucleus • chromosome Biological process • GO:0007126 meiotic cell cycle • reciprocal meiotic recombination • male meiosis I • cell differentiation • oocyte maturation • double-strand break repair • transcription from RNA polymerase II promoter • synaptonemal complex assembly • spermatogenesis • female meiosis I • spermatid development • oogenesis • mitotic spindle assembly checkpoint • regulation of nucleic acid-templated transcription • meiotic recombination checkpoint Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	9319	69716
Ensembl	ENSG00000071539	n/a
UniProt	Q15645	Q3UA06
RefSeq (mRNA)	NM_001166260 NM_004237	NM_027182
RefSeq (protein)	NP_001159732 NP_004228	NP_081458
Location (UCSC)	Chr 5: 0.89 – 0.92 Mb	n/a
PubMed search	[2]	[3]
Wikidata
View/Edit Human View/Edit Mouse

Structure

As an AAA+ ATPase, TRIP13 (and its PCH2 analog) forms homohexamers and interacts with ATP as an energy source. With respect to Hop1, PCH2 binds to and structurally changes Hop1, displacing the Hop1 from DNA.[8] TRIP13/PCH2 interacts with ATP as a hydrolase, hydrolyzing phosphates to derive energy for conformational changes that can induce mechanical force on its substrate, Hop1 in the previous case.[9] TRIP14/PCH2 is believed to have a single AAA+ ATPase domain.[5] TRIP13/PCH2 also functions as a kinetochore protein that interacts with the silencing protein p31-Comet.[10]

Role in meiosis G2/prophase

Meiosis in mammalian cells have a series of checkpoints and steps that need to be properly regulated. TRIP13/PCH2 has been implicated in these processes in budding yeast as well, particularly in the meiosis G2/prophase stage.[11] Double stranded breaks during meiosis is a key part of this phase and is impacted by TRIP13. The homologous recombination that occurs following these breaks requires a protein complex to influence and structure appropriate chromosomal pairing.

In a paper by San-Segundo et al., localization assays and induced mutations in PCH2 in budding yeast was shown to be required for the meiotic checkpoint to prevent chromosome segregation when the recombination or chromosome synapsis are defective.[11] TRIP13, PCH2's analog, was also shown to be required for the formation of the synaptonemal complex – the complex that structures chromosomal pairings. Without TRIP13, meiocytes had pericentric synaptic forks, fewer crossovers, and altered distribution of chiasma (the contact point between homologous chromosomes.[12] For this synaptonemal complex (SC) formation, meiotic HORMADS need to be removed. For example, PCH2 was found to be needed to remove Hop1 from chromosomes during SC formation.[13] Other HORMADs, such as HORMAD1 and HORMAD2, are also depleted from the chromosomal pairs with the help of TRIP13 in mice cells.[14] Research shows a robust and varied role for TRIP13/PCH2 to remove various proteins for SC formation, thus allowing meiosis to continue. Further mechanistic evidence is needed to clarify other proteins affected by TRIP13 in meiosis G2/Prophase, and elucidate the wide ability to affect a multitude of proteins.

Role in spindle assembly checkpoint

Like its role in meiosis, TRIP13/PCH2 is also implicated in mitosis, particularly in the metaphase-to-anaphase transition and the Spindle Assembly Checkpoint (SAC). Its function also has impacts on the Anaphase Promoting Complex (APC).[5] To continue from metaphase to anaphase, the cell must ensure chromosomes are bioriented and properly structured in order for correct and error-free separation of sister chromatids. This process requires many proteins to ensure dynamic timing and consistent response. In order for progression, the APC must be activated, which upon activation degrade securing. The APC is activated by CDC20, a protein that is silenced by the mitotic checkpoint complex (MCC). Of interest in relation to TRIP13 is Mad2, which has two forms (open O-Mad2 and closed C-Mad2)[5] (2). When kinetochores are unattached, O-Mad2 converts to C-Mad2, which is then able to latch to CDC20, and essentially sequester it preventing mitotic progression.[15]

Progression requires the disassembly of the MCC, which is found to be mediated by p31-Comet.[7] This is through to occur in part by structural mimicry, where p31-Comet is structurally similar to C-Mad2.[16] However, this process requires ATP, which is where TRIP13/PCH2 comes into play. Evidence shows that TRIP13/PCH2 uses p31-Comet as an adaptor protein to convert C-Mad2 into O-Mad2.[17] However, the connection between TRIP13/PCH2 and the SAC is more nuanced. Experiments in human HeLa and HCT116 cells show that neither p31-Comet nor TRIP13 was particularly required for unperturbed mitosis, and that depleting P31-Comet only slightly impaired Mad2 inactivation. Additionally, research shows that without TRIP13, Mad2 exists exclusively in the closed form. Interestingly, in TRIP13 deficient cells, the SAC was unable to be inactivated and had a relatively short mitosis. This hints at the possibility that activation of the SAC and the formation of the MCC requires not only C-Mad2 but also the conversion of C-Mad2 to O-Mad2.[6]

Implications in cancer

Given TRIP13/PCH2's role in the correct biorientation of chromosomes during mitosis, it is unsurprising that it is connected to several cancers. In one instance, overexpression of TRIP13 has been shown to affect treatment resistance for Squamous cell carcinoma of the head and neck.[18] Additionally, TRIP13 and Mad2 overexpression are correlated jointly in cancer. In relation to mitotic delays associated with Mad2 overexpression, overexpression of TRIP13 reduced and TRIP13 reduction increased the mitotic delay that Mad2 overexpression brings about. Furthermore, Mad2 over-expression and TRIP13 decrease inhibited proliferation in cells and tumor xenografts – presenting therapeutic value for TRIP13 reduction.[7]

References

1. GRCh38: Ensembl release 89: ENSG00000071539 - Ensembl, May 2017
2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
3. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. Makar AB, McMartin KE, Palese M, Tephly TR (June 1975). "Formate assay in body fluids: application in methanol poisoning". Biochemical Medicine. 13 (2): 117–26. doi:10.1016/0006-2944(75)90147-7. PMID 1.
5. Vader G (September 2015). "Pch2(TRIP13): controlling cell division through regulation of HORMA domains". Chromosoma. 124 (3): 333–9. doi:10.1007/s00412-015-0516-y. PMID 25895724.
6. Ma HT, Poon RY (February 2016). "TRIP13 Regulates Both the Activation and Inactivation of the Spindle-Assembly Checkpoint". Cell Reports. 14 (5): 1086–1099. doi:10.1016/j.celrep.2016.01.001. PMID 26832417.
7. Marks DH, Thomas R, Chin Y, Shah R, Khoo C, Benezra R (May 2017). "Mad2 Overexpression Uncovers a Critical Role for TRIP13 in Mitotic Exit". Cell Reports. 19 (9): 1832–1845. doi:10.1016/j.celrep.2017.05.021. PMC 5526606. PMID 28564602.
8. Chen C, Jomaa A, Ortega J, Alani EE (January 2014). "Pch2 is a hexameric ring ATPase that remodels the chromosome axis protein Hop1". Proceedings of the National Academy of Sciences of the United States of America. 111 (1): E44–53. doi:10.1073/pnas.1310755111. PMC 3890899. PMID 24367111.
9. Yedidi RS, Wendler P, Enenkel C (2017). "AAA-ATPases in Protein Degradation". Frontiers in Molecular Biosciences. 4: 42. doi:10.3389/fmolb.2017.00042. PMC 5476697. PMID 28676851.
10. Tipton AR, Wang K, Oladimeji P, Sufi S, Gu Z, Liu ST (June 2012). "Identification of novel mitosis regulators through data mining with human centromere/kinetochore proteins as group queries". BMC Cell Biology. 13 (1): 15. doi:10.1186/1471-2121-13-15. PMC 3419070. PMID 22712476.
11. San-Segundo PA, Roeder GS (April 1999). "Pch2 links chromatin silencing to meiotic checkpoint control". Cell. 97 (3): 313–24. doi:10.1016/s0092-8674(00)80741-2. PMID 10319812.
12. Roig I, Dowdle JA, Toth A, de Rooij DG, Jasin M, Keeney S (August 2010). "Mouse TRIP13/PCH2 is required for recombination and normal higher-order chromosome structure during meiosis". PLoS Genetics. 6 (8): e1001062. doi:10.1371/journal.pgen.1001062. PMC 2920839. PMID 20711356.
13. Rosenberg SC, Corbett KD (November 2015). "The multifaceted roles of the HORMA domain in cellular signaling". The Journal of Cell Biology. 211 (4): 745–55. doi:10.1083/jcb.201509076. PMC 4657174. PMID 26598612.
14. Wojtasz L, Daniel K, Roig I, Bolcun-Filas E, Xu H, Boonsanay V, Eckmann CR, Cooke HJ, Jasin M, Keeney S, McKay MJ, Toth A (October 2009). "Mouse HORMAD1 and HORMAD2, two conserved meiotic chromosomal proteins, are depleted from synapsed chromosome axes with the help of TRIP13 AAA-ATPase". PLoS Genetics. 5 (10): e1000702. doi:10.1371/journal.pgen.1000702. PMC 2758600. PMID 19851446.
15. Mapelli M, Massimiliano L, Santaguida S, Musacchio A (November 2007). "The Mad2 conformational dimer: structure and implications for the spindle assembly checkpoint" (PDF). Cell. 131 (4): 730–43. doi:10.1016/j.cell.2007.08.049. PMID 18022367.
16. Yang M, Li B, Tomchick DR, Machius M, Rizo J, Yu H, Luo X (November 2007). "p31comet blocks Mad2 activation through structural mimicry". Cell. 131 (4): 744–55. doi:10.1016/j.cell.2007.08.048. PMC 2144745. PMID 18022368.
17. Ye Q, Rosenberg SC, Moeller A, Speir JA, Su TY, Corbett KD (April 2015). "TRIP13 is a protein-remodeling AAA+ ATPase that catalyzes MAD2 conformation switching". eLife. 4. doi:10.7554/eLife.07367. PMC 4439613. PMID 25918846.
18. Banerjee R, Russo N, Liu M, Basrur V, Bellile E, Palanisamy N, Scanlon CS, van Tubergen E, Inglehart RC, Metwally T, Mani RS, Yocum A, Nyati MK, Castilho RM, Varambally S, Chinnaiyan AM, D'Silva NJ (July 2014). "TRIP13 promotes error-prone nonhomologous end joining and induces chemoresistance in head and neck cancer". Nature Communications. 5: 4527. doi:10.1038/ncomms5527. PMC 4130352. PMID 25078033.

Further reading

• Schepens J, Cuppen E, Wieringa B, Hendriks W (June 1997). "The neuronal nitric oxide synthase PDZ motif binds to -G(D,E)XV* carboxyterminal sequences". FEBS Letters. 409 (1): 53–6. doi:10.1016/S0014-5793(97)00481-X. hdl:2066/25057. PMID 9199503.
• Yasugi T, Vidal M, Sakai H, Howley PM, Benson JD (August 1997). "Two classes of human papillomavirus type 16 E1 mutants suggest pleiotropic conformational constraints affecting E1 multimerization, E2 interaction, and interaction with cellular proteins". Journal of Virology. 71 (8): 5942–51. PMC 191850. PMID 9223484.
• Suzuki H, Fukunishi Y, Kagawa I, Saito R, Oda H, Endo T, Kondo S, Bono H, Okazaki Y, Hayashizaki Y (October 2001). "Protein-protein interaction panel using mouse full-length cDNAs". Genome Research. 11 (10): 1758–65. doi:10.1101/gr.180101. PMC 311163. PMID 11591653.
• Kim HJ, Chong KH, Kang SW, Lee JR, Kim JY, Hahn MJ, Kim TJ (September 2004). "Identification of cyclophilin A as a CD99-binding protein by yeast two-hybrid screening". Immunology Letters. 95 (2): 155–9. doi:10.1016/j.imlet.2004.07.001. PMID 15388255.
• Rush J, Moritz A, Lee KA, Guo A, Goss VL, Spek EJ, Zhang H, Zha XM, Polakiewicz RD, Comb MJ (January 2005). "Immunoaffinity profiling of tyrosine phosphorylation in cancer cells". Nature Biotechnology. 23 (1): 94–101. doi:10.1038/nbt1046. PMID 15592455.