Molecular mechanisms in governing genomic stability and tumor suppression by the SETD2 H3K36 methyltransferase

Abstract

Epigenetic dysregulation is an important contributor to carcinogenesis. This is not surprising, as chromatin—genomic DNA organized around structural histone scaffolding—serves as the template on which occurs essential nuclear processes, such as transcription, DNA replication and DNA repair. Histone H3 lysine 36 (H3K36) methyltransferases, such as the SET-domain 2 protein (SETD2), have emerged as critical tumor suppressors. Previous work on mammalian SETD2 and its counterpart in model organisms, Set2, has highlighted the role of this protein in governing genomic stability through transcriptional elongation and splicing, as well as in DNA damage response processes and cell cycle progression. A compendium of SETD2 mutations have been documented, garnered from sequenced cancer patient genome data, and these findings underscore the cancer-driving properties of SETD2 loss-of-function. In this review, we consolidate the molecular mechanisms regulated by SETD2/Set2 and discuss evidence of its dysregulation in tumorigenesis. Insight into the genetic interactions that exist between SETD2 and various canonical intracellular signaling pathways has not only empowered pharmacological intervention by taking advantage of synthetic lethality but underscores SETD2 as a druggable target for precision cancer therapy.