PT - JOURNAL ARTICLE AU - Nehemiah S. Alvarez TI - Epigenetic regulation of DNA repair mediated by the histone methyltransferase DOT1L AID - 10.1101/544981 DP - 2019 Jan 01 TA - bioRxiv PG - 544981 4099 - http://biorxiv.org/content/early/2019/02/09/544981.short 4100 - http://biorxiv.org/content/early/2019/02/09/544981.full AB - In eukaryotic cells, the homologous recombination (HR) and non-homologous end joining (NHEJ) pathways are required for the repair of DNA double strand breaks (DSB). In mammals, histone modification and histone variant exchange into nucleosomes at sites of DSB generate an open chromatin state necessary for repair to take place. How histone modifications contribute to histone variant exchange at DSB sites, and how this process results in DNA repair remain unresolved. Here we show that Disruptor of telomeric silencing āˆ’1 like (DOT1L) is required for H2A.Z histone variant exchange at DSB sites. Cells from Dot1Lāˆ’/āˆ’ mice have increased genomic instability and defects in DNA repair. Loss of either DOT1L or its methylation activity results in decreased H2A.Z incorporation at DSB sites, increased amounts of single strand DNA, and significantly reduced repair activity by homologous recombination.