SETMAR

Histone-lysine N-methyltransferase SETMAR is an enzyme that in humans is encoded by the SETMAR gene.[3][4]

SETMAR
Available structures PDB Human UniProt search: PDBe RCSB List of PDB id codes 3BO5, 3F2K, 3K9J, 3K9K
Identifiers
Aliases	SETMAR, HsMar1, METNASE, Mar1, SET domain and mariner transposase fusion gene
External IDs	OMIM: 609834 HomoloGene: 121979 GeneCards: SETMAR
Gene location (Human) Chr. Chromosome 3 (human)[1] Band 3p26.1 Start 4,303,304 bp[1] End 4,317,567 bp[1]
RNA expression pattern More reference expression data
Gene ontology Molecular function • methyltransferase activity • transferase activity • protein homodimerization activity • zinc ion binding • histone methyltransferase activity (H3-K4 specific) • histone-lysine N-methyltransferase activity • metal ion binding • single-stranded DNA binding • single-stranded DNA endodeoxyribonuclease activity • DNA topoisomerase binding • GO:0001948 protein binding • catalytic activity • nuclease activity • endonuclease activity • histone methyltransferase activity (H3-K36 specific) • double-stranded DNA binding • hydrolase activity • DNA binding Cellular component • site of double-strand break • chromosome • condensed chromosome • cell nucleus • nucleolus Biological process • histone H3-K36 dimethylation • DNA integration • nucleic acid phosphodiester bond hydrolysis • positive regulation of DNA topoisomerase (ATP-hydrolyzing) activity • DNA double-strand break processing • positive regulation of double-strand break repair via nonhomologous end joining • DNA catabolic process, endonucleolytic • cellular response to DNA damage stimulus • negative regulation of cell cycle arrest • histone H3-K36 methylation • histone H3-K4 methylation • methylation • replication fork processing • histone lysine methylation • mitotic DNA integrity checkpoint • metabolism • cellular proliferation • double-strand break repair via nonhomologous end joining • negative regulation of chromosome organization • DNA repair • chromatin organization Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	6419	n/a
Ensembl	ENSG00000170364	n/a
UniProt	Q53H47	n/a
RefSeq (mRNA)	NM_001243723 NM_001276325 NM_006515 NM_001320676 NM_001320677 NM_001320678	n/a
RefSeq (protein)	NP_001230652 NP_001263254 NP_001307605 NP_001307606 NP_001307607 NP_006506	n/a
Location (UCSC)	Chr 3: 4.3 – 4.32 Mb	n/a
PubMed search	[2]	n/a
Wikidata
View/Edit Human

Function

SETMAR contains a SET domain that confers its histone methyltransferase activity, on Lys-4 and Lys-36 of Histone H3, both of which are specific tags for epigenetic activation. It has been identified as a repair protein as it mediates dimethylation at Lys-36 at double-strand break locations, a signal enhancing NHEJ repair.[5][6]

Anthropoid primates, including humans, have a version of the protein fused to a Mariner/Tc1 transposase. This fusion region provides the DNA-binding abilities for the protein as well as some nuclease activity. The transposase activity is lost due to a D610N mutation, but the domain itself can still recognize the mariner repeat elements and introduce nicks in the DNA.[7]

Model organisms

Setmar knockout mouse phenotype

Characteristic	Phenotype
Homozygote viability	Normal
Homozygous Fertility	Normal
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	Abnormal[8]
Clinical chemistry	Normal
Plasma immunoglobulins	Normal
Haematology	Normal
Peripheral blood lymphocytes	Abnormal[9]
Micronucleus test	Normal
Heart weight	Normal
Skin Histopathology	Normal
Brain histopathology	Normal
Salmonella infection	Normal[10]
Citrobacter infection	Normal[11]
All tests and analysis from[12][13]

Model organisms have been used in the study of SETMAR function. A conditional knockout mouse line, called Setmar^{tm1a(EUCOMM)Wtsi}[14][15] 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.[16][17][18] Note that the mouse ortholog is does not have the Tc1/mariner ("MAR") fusion; such a fusion is found only in anthropoid primates. Therefore, the knockout mouse is not for SETMAR but only the SET domain of this chimeric fusion protein.

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[12][19] Twenty five tests were carried out on mutant mice and two significant abnormalities were observed.[12] Homozygous mutant animals of both sex had abnormal retinal pigmentation and morphology, while males also had atypical peripheral blood lymphocyte parameters.[12]

References

1. GRCh38: Ensembl release 89: ENSG00000170364 - Ensembl, May 2017
2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
3. Robertson HM, Zumpano KL (December 1997). "Molecular evolution of an ancient mariner transposon, Hsmar1, in the human genome". Gene. 205 (1–2): 203–17. doi:10.1016/S0378-1119(97)00472-1. PMID 9461395.
4. "Entrez Gene: SETMAR SET domain and mariner transposase fusion gene".
5. Lee SH, Oshige M, Durant ST, Rasila KK, Williamson EA, Ramsey H, Kwan L, Nickoloff JA, Hromas R (December 2005). "The SET domain protein Metnase mediates foreign DNA integration and links integration to nonhomologous end-joining repair". Proceedings of the National Academy of Sciences of the United States of America. 102 (50): 18075–80. Bibcode:2005PNAS..10218075L. doi:10.1073/pnas.0503676102. PMC 1312370. PMID 16332963.
6. Fnu S, Williamson EA, De Haro LP, Brenneman M, Wray J, Shaheen M, Radhakrishnan K, Lee SH, Nickoloff JA, Hromas R (January 2011). "Methylation of histone H3 lysine 36 enhances DNA repair by nonhomologous end-joining". Proceedings of the National Academy of Sciences of the United States of America. 108 (2): 540–5. doi:10.1073/pnas.1013571108. PMC 3021059. PMID 21187428.
7. Miskey C, Papp B, Mátés L, Sinzelle L, Keller H, Izsvák Z, Ivics Z (June 2007). "The ancient mariner sails again: transposition of the human Hsmar1 element by a reconstructed transposase and activities of the SETMAR protein on transposon ends". Molecular and Cellular Biology. 27 (12): 4589–600. doi:10.1128/MCB.02027-06. PMC 1900042. PMID 17403897.
8. "Eye morphology data for Setmar". Wellcome Trust Sanger Institute.
9. "Peripheral blood lymphocytes data for Setmar". Wellcome Trust Sanger Institute.
10. "Salmonella infection data for Setmar". Wellcome Trust Sanger Institute.
11. "Citrobacter infection data for Setmar". Wellcome Trust Sanger Institute.
12. 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. S2CID 85911512.
13. Mouse Resources Portal, Wellcome Trust Sanger Institute.
14. "International Knockout Mouse Consortium".
15. "Mouse Genome Informatics".
16. 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 (June 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–42. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
17. Dolgin E (June 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
18. Collins FS, Rossant J, Wurst W (January 2007). "A mouse for all reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247. S2CID 18872015.
19. van der Weyden L, White JK, Adams DJ, Logan DW (June 2011). "The mouse genetics toolkit: revealing function and mechanism". Genome Biology. 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837. PMID 21722353.

Further reading

• Berry R, Stevens TJ, Walter NA, Wilcox AS, Rubano T, Hopkins JA, Weber J, Goold R, Soares MB, Sikela JM (August 1995). "Gene-based sequence-tagged-sites (STSs) as the basis for a human gene map". Nature Genetics. 10 (4): 415–23. doi:10.1038/ng0895-415. PMID 7670491. S2CID 22277955.
• Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
• Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA (April 1996). "A "double adaptor" method for improved shotgun library construction". Analytical Biochemistry. 236 (1): 107–13. doi:10.1006/abio.1996.0138. PMID 8619474.
• Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G, Gibbs RA (April 1997). "Large-scale concatenation cDNA sequencing". Genome Research. 7 (4): 353–8. doi:10.1101/gr.7.4.353. PMC 139146. PMID 9110174.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
• Lee SH, Oshige M, Durant ST, Rasila KK, Williamson EA, Ramsey H, Kwan L, Nickoloff JA, Hromas R (December 2005). "The SET domain protein Metnase mediates foreign DNA integration and links integration to nonhomologous end-joining repair". Proceedings of the National Academy of Sciences of the United States of America. 102 (50): 18075–80. Bibcode:2005PNAS..10218075L. doi:10.1073/pnas.0503676102. PMC 1312370. PMID 16332963.
• Cordaux R, Udit S, Batzer MA, Feschotte C (May 2006). "Birth of a chimeric primate gene by capture of the transposase gene from a mobile element". Proceedings of the National Academy of Sciences of the United States of America. 103 (21): 8101–6. Bibcode:2006PNAS..103.8101C. doi:10.1073/pnas.0601161103. PMC 1472436. PMID 16672366.
• Keravala A, Liu D, Lechman ER, Wolfe D, Nash JA, Lampe DJ, Robbins PD (October 2006). "Hyperactive Himar1 transposase mediates transposition in cell culture and enhances gene expression in vivo". Human Gene Therapy. 17 (10): 1006–18. doi:10.1089/hum.2006.17.1006. PMID 16989604.
• Liu D, Bischerour J, Siddique A, Buisine N, Bigot Y, Chalmers R (February 2007). "The human SETMAR protein preserves most of the activities of the ancestral Hsmar1 transposase". Molecular and Cellular Biology. 27 (3): 1125–32. doi:10.1128/MCB.01899-06. PMC 1800679. PMID 17130240.
• Miskey C, Papp B, Mátés L, Sinzelle L, Keller H, Izsvák Z, Ivics Z (June 2007). "The ancient mariner sails again: transposition of the human Hsmar1 element by a reconstructed transposase and activities of the SETMAR protein on transposon ends". Molecular and Cellular Biology. 27 (12): 4589–600. doi:10.1128/MCB.02027-06. PMC 1900042. PMID 17403897.
• Roman Y, Oshige M, Lee YJ, Goodwin K, Georgiadis MM, Hromas RA, Lee SH (October 2007). "Biochemical characterization of a SET and transposase fusion protein, Metnase: its DNA binding and DNA cleavage activity". Biochemistry. 46 (40): 11369–76. doi:10.1021/bi7005477. PMC 3374406. PMID 17877369.