Orientation: Plus strand; 68615 bases; Exon count: 30 (NCBI Homo sapiens Annotation Release 108).

7 transcripts for DOT1L are described in the NCBI Nucleotide database. They are predicted by computational analysis. To the best of our knowledge, the functional significance of the different transcripts is to this point unknown. In the mouse, five isoforms have been described (Zhang, W. et al., 2004).

DOT1L includes several domains: catalytic domain (1-332), Bat3-interacting domain (361-380), K-rich patch (390-407) with a partially overlapping NLS (395-417), leucine zipper motif (576-594), CTD binding patch (618-627), three ENL/AF9 binding sites (628-653, 863-878, 877-900), and two more NLSs (1088-1111, 1164-1171) - reviewed in (Vlaming et al., 2016).

DOT1L is thought to predominantly or entirely localize to the nucleus.

DOT1L is the human ortholog of the yeast (S. cerevisiae) gene Disruptor of telomere silencing 1 (Dot1). The gene was reported to be involved in the regulation of telomeric gene silencing and position effect variegation (Singer et al., 1998). Interestingly, more recent data suggest that only select telomeric gene loci are regulated by Dot1 and that H3K79 methylation by Dot1 does not play a role in the maintenance of natural HML silencing but only silences the HM locus in the context of a reporter strain (Takahashi et al., 2011).
The biochemical function of yeast DOT1 and mammalian DOT1L is the methylation of the histone 3 core lysine 79 residue (Feng et al., 2002; Lacoste et al., 2002; Ng et al., 2002; van Leeuwen et al., 2002). DOT1 and hDOT1L methylate nucleosomal substrates, but not free histone H3. They have homology with arginine methyltransferases, but do not contain a SET-domain typical of most lysine methyl-transferases.
Lysine K79me2/3 is thought to be associated with expressed genes. Some evidence suggests antagonism between K79me2/3 and histone 3 lysine 9 methylation-mediated gene silencing mediated by SIRT1 and SUV39H1, which is compatible with prior findings in yeast (Ehrentraut et al., 2011). H3K79 methylation is thought to be linked to cell cycle regulation (Schulze et al., 2009) and to the DNA damage response (Giannattasio et al., 2005).
In bone marrow and leukemia, DOT1L is thought to be important in the regulation of, among other genes, the late HOXA cluster (Bernt et al., 2011; Riedel et al., 2016). In prostate cancer there is evidence for a link between androgen receptor signaling and DOT1L (Yang et al., 2013).

Homolog genes exist in Euteleostomi, with AA and DNA identity of approximately 65 - 99 % (see https://www.ncbi.nlm.nih.gov/homologene/; HomoloGene:32779). Related genes with K79 methyltransferase activity in lower species include the originally discovered yeast (S. cerevisiae) gene Dot1 (Disruptor of telomer silencing 1) (Lacoste et al., 2002; Singer et al., 1998) and the Drosophila ortholog grappa (gpp) (Shanower et al., 2005), mutants of which interestingly exhibit Pc-G phenotypes, but also display phenotypes characteristic of trithorax-group mutants.

Generally speaking, somatic and germline mutations of DOT1L have been identified, but their significance is currently unknown. One published report has suggested a link between Dot1l-mutation and Gastric Cancer (Donner et al., 2015).

A number of germline mutations (missense and loss-of-function) are described in the Exac database (http://exac.broadinstitute.org/gene/ENSG00000104885) . The functional significance is unknown. To the best of our knowledge, there is as yet no human phenotype or syndrome associated with germline DOT1L-mutation.

DOT1L is mutated in a number of human cancers including hematopoietic and solid tumors. The frequency of mutations is typically