Epigenetic regulation of DNA repair mediated by the histone methyltransferase DOT1L

Abstract

The accurate transmission of a genome into future generations, otherwise known as genome integrity, is necessary for life. However, genomic changes due to error or damage are quite common, with an estimated 38,000 DNA base alterations within a cell at any given moment. Thus, genomic integrity depends on high fidelity repair of DNA damage caused by endogenous and exogenous sources. Every cell has machinery that is capable of repairing DNA lesions, and defects in genes encoding DNA repair machinery frequently result in debilitating developmental disorders, cancer, and/or death. There are seven main pathways for DNA repair that have been identified: base excision repair, mismatch repair, nucleotide excision repair, interstrand crosslink repair, single strand break repair, non-homologous end joining, and homologous recombination. Pathway utilization depends on both the type of damage and the stage of the cell cycle. Homologous recombination is an especially important pathway, as it is the sole high fidelity means of repairing double stranded DNA breaks, which are particularly deleterious. It is estimated that ~10 unrepaired double strand breaks are lethal to a cell. The mechanisms that control double strand break repair are incompletely understood, but histone variant H2AZ exchange at DNA damage sites is believed to be an early step in the process and may be regulated by core histone modifications. DOT1-like (DOT1L), the human ortholog of the yeast gene DOT1 (Disruptor of telomeric silencing-1), is a histone H3 (H3K79) methyltransferase and has been implicated in DNA repair. This volume describes the use of both biological and computer science-based approaches to examine the specific function of DOT1L in DNA repair. Cells from DOT1L knockout mice were found to exhibit marked genomic instability and defects in DNA repair. Further, loss of DOT1L and/or its methylation activity resulted in decreased H2AZ incorporation at double strand breaks and increased amounts of single strand DNA, leading to a specific defect in homologous recombination repair activity. Instead, in the absence of either DOT1L or H3K79 methyltransferase activity, the non-homologous end joining repair pathway was utilized, resulting in genomic instability. These findings identify a novel role for DOT1L and H3K79 methylation in facilitating histone exchange at double strand break sites, generating a chromatin state that is permissive for homologous recombination repair. This discovery emphasizes the diverse roles of epigenetic modification in biological processes beyond transcriptional control. Moreover, the identification of DOT1L function in DNA repair provides new opportunities for design and implementation of molecular therapeutics strategies that target DNA repair pathways to treat diseases.