Proposed model of H3K36me3 and DNA damage repair, SETD2 loss, and chemotherapy resistance. (A) The interaction of SETD2 with RNA polymerase leads to high levels of H3K36me3 on expressed genes, which localize several known DNA damage–recognition proteins to the region, even in the absence of DNA damage. DNA damage in those regions is rapidly recognized by local DDR machinery, leading to downstream signaling, including Chk1 phosphorylation and DNA repair and/or apoptosis, and consequently the acquisition of few mutations. In regions of nonexpressed genes, H3K36me3 is low and there is relatively less localization of DDR machinery. This leads to relatively less DDR activation, and DNA damage goes unrecognized and unrepaired, leading to cell survival with concurrent mutations. (B) In wild-type cells, chemotherapy-induced DNA damage triggers DDR, resulting in some repair, but significant apoptosis. In SETD2-mutant cells, the relative lack of DDR results in less repair, but also less apoptosis, leading to the survival of mutated cells.