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// Danielle P. Johnson 2,* , Gabriella S. Spitz 1,* , Shweta Tharkar 1 , Steven N. Quayle 3 , Jeffrey R. Shearstone 3 , Simon Jones 3 , Maria E. McDowell 1 , Hannah Wellman 1 , Jessica K. Tyler 4 , Bradley R. Cairns 2 , Mahesh B. Chandrasekharan 1 and Srividya Bhaskara 1,2 1 Department of Radiation Oncology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 2 Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 3 Acetylon Pharmaceuticals, Inc., Boston, MA 4 Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, TX * These authors contributed equally to the study Correspondence: Srividya Bhaskara, email: // Keywords : epigenetics, DNA repair, HDAC1,2, chromatin, EZH2 Received : November 01, 2014 Accepted : December 28, 2014 Published : December 31, 2014 Abstract Gain-of-function mutations in the catalytic site of EZH2 (Enhancer of Zeste Homologue 2), is observed in about 22% of diffuse large B-cell lymphoma (DLBCL) cases. Here we show that selective inhibition of histone deacetylase 1,2 (HDAC1,2) activity using a small molecule inhibitor causes cytotoxic or cytostatic effects in EZH2 gain-of-function mutant (EZH2 GOF ) DLBCL cells. Our results show that blocking the activity of HDAC1,2 increases global H3K27ac without causing a concomitant global decrease in H3K27me3 levels. Our data shows that inhibition of HDAC1,2 is sufficient to decrease H3K27me3 present at DSBs, decrease DSB repair and activate the DNA damage response in these cells. In addition to increased H3K27me3, we found that the EZH2 GOF DLBCL cells overexpress another chemotherapy resistance factor − B-lymphoma and BAL-associated protein (BBAP). BBAP monoubiquitinates histone H4K91, a residue that is also subjected to acetylation. Our results show that selective inhibition of HDAC1,2 increases H4K91ac, decreases BBAP-mediated H4K91 monoubiquitination, impairs BBAP-dependent DSB repair and sensitizes the refractory EZH2 GOF DLBCL cells to treatment with doxorubicin, a chemotherapy agent. Hence, selective HDAC1,2 inhibition provides a novel DNA repair mechanism-based therapeutic approach as it can overcome both EZH2- and BBAP-mediated DSB repair in the EZH2 GOF DLBCL cells.