SETMAR

Last updated
SETMAR
Protein SETMAR PDB 3BO5.png
Available structures
PDB Human UniProt search: PDBe RCSB
Identifiers
Aliases SETMAR , HsMar1, METNASE, Mar1, SET domain and mariner transposase fusion gene
External IDs OMIM: 609834 HomoloGene: 121979 GeneCards: SETMAR
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

n/a

RefSeq (protein)

n/a

Location (UCSC) Chr 3: 4.3 – 4.32 Mb n/a
PubMed search [2] n/a
Wikidata
View/Edit Human

Histone-lysine N-methyltransferase SETMAR is an enzyme that in humans is encoded by the SETMAR gene. [3] [4] [5] [6]

Contents

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. [7] [8]

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 the presence of several inactivating mutations, [9] including the D610N mutation. [10] [11] However, the domesticated transposase domain retains its ability to bind to the mariner repeat elements in the genome. [12] [13] [14] [15] SETMAR has been found to affect the expression and splicing of genes close to or containing mariner repeat elements via its functions in histone methylation. [12] [13] [15] Both the SET, via its methyltransferase activity, [7] [8] [16] and the mariner, with its DNA-binding [17] and nuclease activities, [18] [19] [20] [21] [16] domains of SETMAR have been shown to act in non-homologous end joining (NHEJ) to repair DNA double strand breaks.

Related Research Articles

<span class="mw-page-title-main">Transposable element</span> Semiparasitic DNA sequence

A transposable element is a nucleic acid sequence in DNA that can change its position within a genome, sometimes creating or reversing mutations and altering the cell's genetic identity and genome size. Transposition often results in duplication of the same genetic material. In the human genome, L1 and Alu elements are two examples. Barbara McClintock's discovery of them earned her a Nobel Prize in 1983. Its importance in personalized medicine is becoming increasingly relevant, as well as gaining more attention in data analytics given the difficulty of analysis in very high dimensional spaces.

A transposase is any of a class of enzymes capable of binding to the end of a transposon and catalysing its movement to another part of a genome, typically by a cut-and-paste mechanism or a replicative mechanism, in a process known as transposition. The word "transposase" was first coined by the individuals who cloned the enzyme required for transposition of the Tn3 transposon. The existence of transposons was postulated in the late 1940s by Barbara McClintock, who was studying the inheritance of maize, but the actual molecular basis for transposition was described by later groups. McClintock discovered that some segments of chromosomes changed their position, jumping between different loci or from one chromosome to another. The repositioning of these transposons allowed other genes for pigment to be expressed. Transposition in maize causes changes in color; however, in other organisms, such as bacteria, it can cause antibiotic resistance. Transposition is also important in creating genetic diversity within species and generating adaptability to changing living conditions.

<span class="mw-page-title-main">Non-homologous end joining</span> Pathway that repairs double-strand breaks in DNA

Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. It is called "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology directed repair (HDR), which requires a homologous sequence to guide repair. NHEJ is active in both non-dividing and proliferating cells, while HDR is not readily accessible in non-dividing cells. The term "non-homologous end joining" was coined in 1996 by Moore and Haber.

The Sleeping Beauty transposon system is a synthetic DNA transposon designed to introduce precisely defined DNA sequences into the chromosomes of vertebrate animals for the purposes of introducing new traits and to discover new genes and their functions. It is a Tc1/mariner-type system, with the transposase resurrected from multiple inactive fish sequences.

<span class="mw-page-title-main">EHMT1</span> Protein-coding gene in the species Homo sapiens

Euchromatic histone-lysine N-methyltransferase 1, also known as G9a-like protein (GLP), is a protein that in humans is encoded by the EHMT1 gene.

<span class="mw-page-title-main">Cancer epigenetics</span> Field of study in cancer research

Cancer epigenetics is the study of epigenetic modifications to the DNA of cancer cells that do not involve a change in the nucleotide sequence, but instead involve a change in the way the genetic code is expressed. Epigenetic mechanisms are necessary to maintain normal sequences of tissue specific gene expression and are crucial for normal development. They may be just as important, if not even more important, than genetic mutations in a cell's transformation to cancer. The disturbance of epigenetic processes in cancers, can lead to a loss of expression of genes that occurs about 10 times more frequently by transcription silencing than by mutations. As Vogelstein et al. points out, in a colorectal cancer there are usually about 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations. However, in colon tumors compared to adjacent normal-appearing colonic mucosa, there are about 600 to 800 heavily methylated CpG islands in the promoters of genes in the tumors while these CpG islands are not methylated in the adjacent mucosa. Manipulation of epigenetic alterations holds great promise for cancer prevention, detection, and therapy. In different types of cancer, a variety of epigenetic mechanisms can be perturbed, such as the silencing of tumor suppressor genes and activation of oncogenes by altered CpG island methylation patterns, histone modifications, and dysregulation of DNA binding proteins. There are several medications which have epigenetic impact, that are now used in a number of these diseases.

<span class="mw-page-title-main">Conservative transposition</span>

Transposition is the process by which a specific genetic sequence, known as a transposon, is moved from one location of the genome to another. Simple, or conservative transposition, is a non-replicative mode of transposition. That is, in conservative transposition the transposon is completely removed from the genome and reintegrated into a new, non-homologous locus, the same genetic sequence is conserved throughout the entire process. The site in which the transposon is reintegrated into the genome is called the target site. A target site can be in the same chromosome as the transposon or within a different chromosome. Conservative transposition uses the "cut-and-paste" mechanism driven by the catalytic activity of the enzyme transposase. Transposase acts like DNA scissors; it is an enzyme that cuts through double-stranded DNA to remove the transposon, then transfers and pastes it into a target site.

DNA transposons are DNA sequences, sometimes referred to "jumping genes", that can move and integrate to different locations within the genome. They are class II transposable elements (TEs) that move through a DNA intermediate, as opposed to class I TEs, retrotransposons, that move through an RNA intermediate. DNA transposons can move in the DNA of an organism via a single-or double-stranded DNA intermediate. DNA transposons have been found in both prokaryotic and eukaryotic organisms. They can make up a significant portion of an organism's genome, particularly in eukaryotes. In prokaryotes, TE's can facilitate the horizontal transfer of antibiotic resistance or other genes associated with virulence. After replicating and propagating in a host, all transposon copies become inactivated and are lost unless the transposon passes to a genome by starting a new life cycle with horizontal transfer. It is important to note that DNA transposons do not randomly insert themselves into the genome, but rather show preference for specific sites.

H3K4me3 is an epigenetic modification to the DNA packaging protein Histone H3 that indicates tri-methylation at the 4th lysine residue of the histone H3 protein and is often involved in the regulation of gene expression. The name denotes the addition of three methyl groups (trimethylation) to the lysine 4 on the histone H3 protein.

Tc1/mariner is a class and superfamily of interspersed repeats DNA transposons. The elements of this class are found in all animals, including humans. They can also be found in protists and bacteria.

H3K9me3 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the tri-methylation at the 9th lysine residue of the histone H3 protein and is often associated with heterochromatin.

H3K4me1 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the mono-methylation at the 4th lysine residue of the histone H3 protein and often associated with gene enhancers.

H3K36me3 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the tri-methylation at the 36th lysine residue of the histone H3 protein and often associated with gene bodies.

H3K79me2 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the di-methylation at the 79th lysine residue of the histone H3 protein. H3K79me2 is detected in the transcribed regions of active genes.

H4K20me is an epigenetic modification to the DNA packaging protein Histone H4. It is a mark that indicates the mono-methylation at the 20th lysine residue of the histone H4 protein. This mark can be di- and tri-methylated. It is critical for genome integrity including DNA damage repair, DNA replication and chromatin compaction.

H3K36me is an epigenetic modification to the DNA packaging protein Histone H3, specifically, the mono-methylation at the 36th lysine residue of the histone H3 protein.

H3R42me is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates the mono-methylation at the 42nd arginine residue of the histone H3 protein. In epigenetics, arginine methylation of histones H3 and H4 is associated with a more accessible chromatin structure and thus higher levels of transcription. The existence of arginine demethylases that could reverse arginine methylation is controversial.

H3R26me2 is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates the di-methylation at the 26th arginine residue of the histone H3 protein. In epigenetics, arginine methylation of histones H3 and H4 is associated with a more accessible chromatin structure and thus higher levels of transcription. The existence of arginine demethylases that could reverse arginine methylation is controversial.

H3R2me2 is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates the di-methylation at the 2nd arginine residue of the histone H3 protein. In epigenetics, arginine methylation of histones H3 and H4 is associated with a more accessible chromatin structure and thus higher levels of transcription. The existence of arginine demethylases that could reverse arginine methylation is controversial.

H4R3me2 is an epigenetic modification to the DNA packaging protein histone H4. It is a mark that indicates the di-methylation at the 3rd arginine residue of the histone H4 protein. In epigenetics, arginine methylation of histones H3 and H4 is associated with a more accessible chromatin structure and thus higher levels of transcription. The existence of arginine demethylases that could reverse arginine methylation is controversial.

References

  1. 1 2 3 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): 203–217. doi:10.1016/S0378-1119(97)00472-1. PMID   9461395.
  4. "Entrez Gene: SETMAR SET domain and mariner transposase fusion gene".
  5. Tellier M (December 2021). "Structure, Activity, and Function of SETMAR Protein Lysine Methyltransferase". Life. 11 (12): 1342. Bibcode:2021Life...11.1342T. doi: 10.3390/life11121342 . PMC   8704517 . PMID   34947873.
  6. Lié O, Renault S, Augé-Gouillou C (April 2022). "SETMAR, a case of primate co-opted genes: towards new perspectives". Mobile DNA. 13 (1): 9. doi: 10.1186/s13100-022-00267-1 . PMC   8994322 . PMID   35395947.
  7. 1 2 Lee SH, Oshige M, Durant ST, Rasila KK, Williamson EA, Ramsey H, et al. (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): 18075–18080. Bibcode:2005PNAS..10218075L. doi: 10.1073/pnas.0503676102 . PMC   1312370 . PMID   16332963.
  8. 1 2 Fnu S, Williamson EA, De Haro LP, Brenneman M, Wray J, Shaheen M, et al. (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): 540–545. Bibcode:2011PNAS..108..540F. doi: 10.1073/pnas.1013571108 . PMC   3021059 . PMID   21187428.
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  10. 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): 4589–4600. doi:10.1128/MCB.02027-06. PMC   1900042 . PMID   17403897.
  11. 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): 1125–1132. doi:10.1128/MCB.01899-06. PMC   1800679 . PMID   17130240.
  12. 1 2 Tellier M, Chalmers R (January 2019). "Human SETMAR is a DNA sequence-specific histone-methylase with a broad effect on the transcriptome". Nucleic Acids Research. 47 (1): 122–133. doi:10.1093/nar/gky937. PMC   6326780 . PMID   30329085.
  13. 1 2 Antoine-Lorquin A, Arensburger P, Arnaoty A, Asgari S, Batailler M, Beauclair L, et al. (May 2021). "Two repeated motifs enriched within some enhancers and origins of replication are bound by SETMAR isoforms in human colon cells". Genomics. 113 (3): 1589–1604. doi: 10.1016/j.ygeno.2021.03.032 . PMID   33812898. S2CID   233028866.
  14. Miskei M, Horváth A, Viola L, Varga L, Nagy É, Feró O, et al. (2021-01-01). "Genome-wide mapping of binding sites of the transposase-derived SETMAR protein in the human genome". Computational and Structural Biotechnology Journal. 19: 4032–4041. doi:10.1016/j.csbj.2021.07.010. PMC   8327481 . PMID   34377368.
  15. 1 2 Chen Q, Bates AM, Hanquier JN, Simpson E, Rusch DB, Podicheti R, et al. (May 2022). "Structural and genome-wide analyses suggest that transposon-derived protein SETMAR alters transcription and splicing". The Journal of Biological Chemistry. 298 (5): 101894. doi: 10.1016/j.jbc.2022.101894 . PMC   9062482 . PMID   35378129.
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  18. Hromas R, Wray J, Lee SH, Martinez L, Farrington J, Corwin LK, et al. (December 2008). "The human set and transposase domain protein Metnase interacts with DNA Ligase IV and enhances the efficiency and accuracy of non-homologous end-joining". DNA Repair. 7 (12): 1927–1937. doi:10.1016/j.dnarep.2008.08.002. PMC   2644637 . PMID   18773976.
  19. Beck BD, Lee SS, Williamson E, Hromas RA, Lee SH (May 2011). "Biochemical characterization of metnase's endonuclease activity and its role in NHEJ repair". Biochemistry. 50 (20): 4360–4370. doi:10.1021/bi200333k. PMC   3388547 . PMID   21491884.
  20. Mohapatra S, Yannone SM, Lee SH, Hromas RA, Akopiants K, Menon V, et al. (June 2013). "Trimming of damaged 3' overhangs of DNA double-strand breaks by the Metnase and Artemis endonucleases". DNA Repair. 12 (6): 422–432. doi:10.1016/j.dnarep.2013.03.005. PMC   3660496 . PMID   23602515.
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Further reading