Dot1-like protein (DOT1L) is an evolutionarily conserved histone 
methyltransferase that methylates lysine 79 of histone H3 (H3K79). Mammalian 
DOT1L participates in the regulation of transcription, development, 
erythropoiesis, differentiation, and proliferation of normal cells. However, the 
role of DOT1L in cancer cell proliferation has not been fully elucidated. DOT1L 
siRNA-transfected A549 or NCI-H1299 lung cancer cells displayed a 
nonproliferating multinucleated phenotype. DOT1L-deficient cells also showed 
abnormal mitotic spindle formation and centrosome number, suggesting that DOT1L 
deficiency leads to chromosomal missegregation. This chromosomal instability in 
DOT1L-deficient cells led to cell cycle arrest at the G(1) phase and induced 
senescence as determined by enhanced activity of senescence-associated 
β-galactosidase activity. Meanwhile, overexpression of a catalytically active 
DOT1L, not an inactive mutant, restored DOT1L siRNA-induced phenotypes. Overall, 
these data imply that down-regulation of DOT1L-mediated H3K79 methylation 
disturbs proliferation of human cells. In addition, although H3K79 methylation 
is down-regulated in aged tissues, it is up-regulated in lung cancer cell lines 
and tumor tissues of lung cancer patients. Therefore, H3K79 methylation is a 
critical histone modification that regulates cell proliferation and would be a 
novel histone mark for aging and cancer.