Roles of SETD2 in Leukemia—Transcription, DNA-Damage, and Beyond

Abstract

The non-redundant histone methyltransferase SETD2 (SET domain containing 2; KMT3A) is responsible for tri-methylation of lysine 36 on histone H3 (H3K36me3). Presence of the H3K36me3 histone mark across the genome has been correlated with transcriptional activation and elongation, but also with the regulation of DNA mismatch repair, homologous recombination and alternative splicing. The role of SETD2 and the H3K36me3 histone mark in cancer is controversial. SETD2 is lost or mutated in various cancers, supporting a tumor suppressive role of the protein. Alterations in the SETD2 gene are also present in leukemia patients, where they are associated with aggressive disease and relapse. In line, heterozygous SETD2 loss caused chemotherapy resistance in leukemia cell lines and mouse models. In contrast, other studies indicate that SETD2 is critically required for the proliferation of leukemia cells. Thus, although studies of SETD2-dependent processes in cancer have contributed to a better understanding of the SETD2–H3K36me3 axis, many open questions remain regarding its specific role in leukemia. Here, we review the current literature about critical functions of SETD2 in the context of hematopoietic malignancies.

SETD2 reduction adversely affects the development of mouse early embryos

“…16,23 Herein, the methylation status of histone H3K36me3 was measured in early embryo devoid of SETD2. 6,17 In this study, we explored the function of SETD2 in early embryos. As shown in Figure 5, H3K36me3 signals in the nucleus were dramatically reduced when SETD2 was depleted.…”

“…SETD2, SET domain-containing protein 2; γ-H2AX, phosphorylated histone H2AX SETD2, as the methyltransferase for histone H3K36, involves in chromatin architecture maintenance, transcriptional activation and elongation, and the regulation of DNA repair to ensure normal cell viability. 6,17 In this study, we explored the function of SETD2 in early embryos. Notably, SETD2 knockdown induces the increased DNA lesions in preimplantation embryos ( Figure 3).…”

“…5,6 Functions of SETD2, from yeast to humans, are highly conserved. [15][16][17] H3K36me3 also participates in promoting de novo DNA methylation. 10 Pathogenic mutations in SETD2 were detected in cancers, including renal cell carcinomas, lung cancer, acute lymphoblastic leukemia, and central nervous system tumors.…”

H3K36me3, message from chromatin to DNA damage repair

“…Besides the role in DNA damage repair, SETD2 is also required to maintain high H3K79me2 levels in AML cells. Pharmacologic inhibition of DOT1L, the H3K79 methyltransferase, synergizes with SETD2 mutations to induce DNA damage, growth arrest, and apoptosis, indicating a cross-talk of H3K36me3 and H3K79me2 in AML cells [86,87].…”

Histone methyltransferase and drug resistance in cancers

“…For example, SMYD2 catalyzes p53 lysine 370 methylation to affect transcription [15]. The detail functions and mechanisms of KMTs and PRMTs can be found in pulished studies [27,28].…”