DOT1L

Last updated

DOT1L
Protein DOT1L PDB 1nw3.png
Available structures
PDB Human UniProt search: PDBe RCSB
Identifiers
Aliases DOT1L , DOT1, KMT4, DOT1 like histone lysine methyltransferase
External IDs OMIM: 607375; MGI: 2143886; HomoloGene: 32779; GeneCards: DOT1L; OMA:DOT1L - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_032482

NM_199322

RefSeq (protein)

NP_115871

n/a

Location (UCSC) Chr 19: 2.16 – 2.23 Mb Chr 10: 80.59 – 80.63 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

DOT1-like (Disruptor of telomeric silencing 1-like), histone H3K79 methyltransferase (S. cerevisiae), also known as DOT1L, is a protein found in humans, as well as other eukaryotes. [5]

DOT1L has been reported to play an important role in the processes of mixed-lineage leukemia (MLL)-rearranged leukemias. [6] DOT1L also plays a role in spermatogenesis, where it acts as a transcriptional activator for genes responsible for the histone-to-protamine transition. [7]

Small molecule inhibitors of Dot1L catalytic activity have been developed. [8] [9]

All three forms of H3K79 methylation (H3K79me1; H3K79me2; H3K79me3) are catalyzed by DOT1 in yeast or DOT1L in mammals. H3K79 methylation participates in the DNA damage response and has multiple roles in nucleotide excision repair and sister chromatid recombinational repair. [10]

Related Research Articles

<span class="mw-page-title-main">Histone</span> Protein family around which DNA winds to form nucleosomes

In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei and in most Archaeal phyla. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are wrapped into 30-nanometer fibers that form tightly packed chromatin. Histones prevent DNA from becoming tangled and protect it from DNA damage. In addition, histones play important roles in gene regulation and DNA replication. Without histones, unwound DNA in chromosomes would be very long. For example, each human cell has about 1.8 meters of DNA if completely stretched out; however, when wound about histones, this length is reduced to about 90 micrometers (0.09 mm) of 30 nm diameter chromatin fibers.

<span class="mw-page-title-main">Histone methyltransferase</span> Histone-modifying enzymes

Histone methyltransferases (HMT) are histone-modifying enzymes, that catalyze the transfer of one, two, or three methyl groups to lysine and arginine residues of histone proteins. The attachment of methyl groups occurs predominantly at specific lysine or arginine residues on histones H3 and H4. Two major types of histone methyltranferases exist, lysine-specific and arginine-specific. In both types of histone methyltransferases, S-Adenosyl methionine (SAM) serves as a cofactor and methyl donor group.
The genomic DNA of eukaryotes associates with histones to form chromatin. The level of chromatin compaction depends heavily on histone methylation and other post-translational modifications of histones. Histone methylation is a principal epigenetic modification of chromatin that determines gene expression, genomic stability, stem cell maturation, cell lineage development, genetic imprinting, DNA methylation, and cell mitosis.

Histone methylation is a process by which methyl groups are transferred to amino acids of histone proteins that make up nucleosomes, which the DNA double helix wraps around to form chromosomes. Methylation of histones can either increase or decrease transcription of genes, depending on which amino acids in the histones are methylated, and how many methyl groups are attached. Methylation events that weaken chemical attractions between histone tails and DNA increase transcription because they enable the DNA to uncoil from nucleosomes so that transcription factor proteins and RNA polymerase can access the DNA. This process is critical for the regulation of gene expression that allows different cells to express different genes.

<span class="mw-page-title-main">KDM1A</span> Protein-coding gene in the species Homo sapiens

Lysine-specific histone demethylase 1A (LSD1) also known as lysine (K)-specific demethylase 1A (KDM1A) is a protein that in humans is encoded by the KDM1A gene. LSD1 is a flavin-dependent monoamine oxidase, which can demethylate mono- and di-methylated lysines, specifically histone 3, lysine 4 (H3K4). Other reported methylated lysine substrates such as histone H3K9 and TP53 have not been biochemically validated. This enzyme plays a critical role in oocyte growth, embryogenesis, hematopoiesis and tissue-specific differentiation. LSD1 was the first histone demethylase to be discovered though more than 30 have since been described.

<span class="mw-page-title-main">DNMT3B</span> Protein-coding gene in the species Homo sapiens

DNA (cytosine-5)-methyltransferase 3 beta, is an enzyme that in humans in encoded by the DNMT3B gene. Mutation in this gene are associated with immunodeficiency, centromere instability and facial anomalies syndrome.

<span class="mw-page-title-main">EZH2</span> Protein-coding gene in the species Homo sapiens

Enhancer of zeste homolog 2 (EZH2) is a histone-lysine N-methyltransferase enzyme encoded by EZH2 gene, that participates in histone methylation and, ultimately, transcriptional repression. EZH2 catalyzes the addition of methyl groups to histone H3 at lysine 27, by using the cofactor S-adenosyl-L-methionine. Methylation activity of EZH2 facilitates heterochromatin formation thereby silences gene function. Remodeling of chromosomal heterochromatin by EZH2 is also required during cell mitosis.

<span class="mw-page-title-main">DNA (cytosine-5)-methyltransferase 3A</span> Protein-coding gene in the species Homo sapiens

DNA (cytosine-5)-methyltransferase 3A (DNMT3A) is an enzyme that catalyzes the transfer of methyl groups to specific CpG structures in DNA, a process called DNA methylation. The enzyme is encoded in humans by the DNMT3A gene.

<span class="mw-page-title-main">KMT2A</span> Protein-coding gene in the species Homo sapiens

Histone-lysine N-methyltransferase 2A, also known as acute lymphoblastic leukemia 1 (ALL-1), myeloid/lymphoid or mixed-lineage leukemia1 (MLL1), or zinc finger protein HRX (HRX), is an enzyme that in humans is encoded by the KMT2A gene.

<span class="mw-page-title-main">SETDB1</span> Enzyme-coding gene in humans

Histone-lysine N-methyltransferase SETDB1 is an enzyme that in humans is encoded by the SETDB1 gene. SETDB1 is also known as KMT1E or H3K9 methyltransferase ESET.

<span class="mw-page-title-main">HIST2H3PS2</span> Pseudogene in the species Homo sapiens

Histone cluster 2, H3, pseudogene 2, also known as HIST2H3PS2, is a human gene.

<span class="mw-page-title-main">KMT2C</span> Protein-coding gene in the species Homo sapiens

Lysine N-methyltransferase 2C (KMT2C) also known as myeloid/lymphoid or mixed-lineage leukemia protein 3 (MLL3) is an enzyme that in humans is encoded by the KMT2C gene.

<span class="mw-page-title-main">Histone H3.1</span> Protein-coding gene in the species Homo sapiens

Histone H3.1 is a protein in humans that is encoded by the H3C1 gene.

<span class="mw-page-title-main">HIST1H3F</span> Protein-coding gene in the species Homo sapiens

Histone H3.1 is a protein that in humans is encoded by the HIST1H3F gene.

<span class="mw-page-title-main">SETD7</span> Protein-coding gene in the species Homo sapiens

Histone-lysine N-methyltransferase SETD7 is an enzyme that in humans is encoded by the SETD7 gene.

<span class="mw-page-title-main">SETD2</span> Protein-coding gene in the species Homo sapiens

SET domain containing 2 is an enzyme that in humans is encoded by the SETD2 gene.

<span class="mw-page-title-main">KMT2D</span> Protein-coding gene in humans

Histone-lysine N-methyltransferase 2D (KMT2D), also known as MLL4 and sometimes MLL2 in humans and Mll4 in mice, is a major mammalian histone H3 lysine 4 (H3K4) mono-methyltransferase. It is part of a family of six Set1-like H3K4 methyltransferases that also contains KMT2A, KMT2B, KMT2C, KMT2F, and KMT2G.

<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.

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.

H3K9me2 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the di-methylation at the 9th lysine residue of the histone H3 protein. H3K9me2 is strongly associated with transcriptional repression. H3K9me2 levels are higher at silent compared to active genes in a 10kb region surrounding the transcriptional start site. H3K9me2 represses gene expression both passively, by prohibiting acetylation as therefore binding of RNA polymerase or its regulatory factors, and actively, by recruiting transcriptional repressors. H3K9me2 has also been found in megabase blocks, termed Large Organised Chromatin K9 domains (LOCKS), which are primarily located within gene-sparse regions but also encompass genic and intergenic intervals. Its synthesis is catalyzed by G9a, G9a-like protein, and PRDM2. H3K9me2 can be removed by a wide range of histone lysine demethylases (KDMs) including KDM1, KDM3, KDM4 and KDM7 family members. H3K9me2 is important for various biological processes including cell lineage commitment, the reprogramming of somatic cells to induced pluripotent stem cells, regulation of the inflammatory response, and addiction to drug use.

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.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000104885 Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000061589 Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. "Entrez Gene: DOT1L DOT1-like, histone H3 methyltransferase (S. cerevisiae)".
  6. Slany RK (October 2016). "The molecular mechanics of mixed lineage leukemia". Oncogene. 35 (40): 5215–5223. doi: 10.1038/onc.2016.30 . PMID   26923329. S2CID   34116587.
  7. Malla AB, Rainsford SR, Smith ZD, Lesch BJ (May 2023). "DOT1L promotes spermatid differentiation by regulating expression of genes required for histone-to-protamine replacement". Development. 150 (9). doi:10.1242/dev.201497. PMC   10259660 . PMID   37082969.
  8. Yao Y, Chen P, Diao J, Cheng G, Deng L, Anglin JL, et al. (2011). "Selective inhibitors of histone methyltransferase DOT1L: design, synthesis, and crystallographic studies". Journal of the American Chemical Society. 133 (42): 16746–9. doi:10.1021/ja206312b. PMC   3492951 . PMID   21936531.
  9. Chen S, Li L, Chen Y, Hu J, Liu J, Liu YC, et al. (2016). "Identification of Novel Disruptor of Telomeric Silencing 1-like (DOT1L) Inhibitors through Structure-Based Virtual Screening and Biological Assays". Journal of Chemical Information and Modeling. 56 (3): 527–34. doi:10.1021/acs.jcim.5b00738. PMID   26914852.
  10. Chen Y, Zhu WG (July 2016). "Biological function and regulation of histone and non-histone lysine methylation in response to DNA damage". Acta Biochim. Biophys. Sin. (Shanghai). 48 (7): 603–16. doi: 10.1093/abbs/gmw050 . PMID   27217472.

Further reading