The Relationship Between DOT1L, Histone H3 Methylation, and Genome Stability in Cancer

Abstract

This review describes how disruptor of telomeric silencing 1-like (DOT1L) and histone H3 at lysine 79 (H3K79) methylation maintain genome stability under normal conditions and discusses the consequences of their dysregulation. We highlight the roles that DOT1L and H3K79 methylation have in various cellular processes and detail their roles in the DNA damage response and mitotic fidelity. DOT1L is currently the only known enzyme capable of catalyzing the methylation of H3K79. DOT1L activity and H3K79 methylation regulate a number of key cellular processes required to maintain genome stability, including transcription, cell cycle progression, and the DNA damage response. Consequently, alterations of DOT1L activity and H3K79 methylation patterning are predicted to compromise genome stability. Consistent with a putative role in oncogenesis, aberrant DOT1L expression and function occur in a wide range of cancer types including breast, colorectal, and lung, yet the exact mechanisms linking altered DOT1L expression and H3K79 methylation to genome instability remain poorly understood.