Substrate and Product Specificities of SET Domain Methyltransferases

Overview

Journal Epigenetics

Specialty Genetics

Date 2011 Aug 18

PMID 21847010

Citations 64

Authors

Paul A Del Rizzo

Raymond C Trievel

Affiliations

Soon will be listed here.

Abstract

SET domain lysine methyltransferases (KMTs) catalyze the site- and state-specific methylation of lysine residues in histone and non-histone substrates. These modifications play fundamental roles in transcriptional regulation, heterochromatin formation, X chromosome inactivation and DNA damage response, and have been implicated in the epigenetic regulation of cell identity and fate. The substrate and product specificities of SET domain KMTs are pivotal to eliciting these effects due to the distinct functions associated with site and state-specific protein lysine methylation. Here, we review advances in understanding the molecular basis of these specificities gained through structural and biochemical studies of the human methyltransferases Mixed Lineage Leukemia 1 (MLL1, also known as KMT2A) and SET7/9 (KMT7). We conclude by exploring the broader implications of these findings on the biological functions of protein lysine methylation by SET domain KMTs.

Citing Articles

The SET29 and SET7 proteins of Leishmania donovani exercise non-redundant convergent as well as collaborative functions in moderating the parasite's response to oxidative stress.

Sharma V, Pal J, Dashora V, Chattopadhyay S, Kapoor Y, Singha B J Biol Chem. 2025; 301(3):108208.

PMID: 39842664 PMC: 11871502. DOI: 10.1016/j.jbc.2025.108208.

SETD7 promotes LC3B methylation and degradation in ovarian cancer.

Zhang Z, Li M, Hou Y, Huang T, Zhang B, Lin Q J Biol Chem. 2024; 301(2):108134.

PMID: 39725038 PMC: 11791264. DOI: 10.1016/j.jbc.2024.108134.

Menin inhibitors for the treatment of acute myeloid leukemia: challenges and opportunities ahead.

Nadiminti K, Sahasrabudhe K, Liu H J Hematol Oncol. 2024; 17(1):113.

PMID: 39558390 PMC: 11575055. DOI: 10.1186/s13045-024-01632-8.

Comparative genome-wide identification and characterization of SET domain-containing and JmjC domain-containing proteins in piroplasms.

Liang Q, Zhang S, Liu Z, Wang J, Yin H, Guan G BMC Genomics. 2024; 25(1):804.

PMID: 39187768 PMC: 11346185. DOI: 10.1186/s12864-024-10731-2.

KMT2A and chronic inflammation as potential drivers of sporadic parathyroid adenoma.

Xu Q, La T, Ye K, Wang L, Wang S, Hu Y Clin Transl Med. 2024; 14(6):e1734.

PMID: 38888967 PMC: 11185127. DOI: 10.1002/ctm2.1734.

References

Wilson J, Jing C, Walker P, Martin S, Howell S, Blackburn G . Crystal structure and functional analysis of the histone methyltransferase SET7/9. Cell. 2002; 111(1):105-15. DOI: 10.1016/s0092-8674(02)00964-9. View

Dillon S, Zhang X, Trievel R, Cheng X . The SET-domain protein superfamily: protein lysine methyltransferases. Genome Biol. 2005; 6(8):227. PMC: 1273623. DOI: 10.1186/gb-2005-6-8-227. View

Dou Y, Hess J . Mechanisms of transcriptional regulation by MLL and its disruption in acute leukemia. Int J Hematol. 2008; 87(1):10-8. DOI: 10.1007/s12185-007-0009-8. View

Song J, Kingston R . WDR5 interacts with mixed lineage leukemia (MLL) protein via the histone H3-binding pocket. J Biol Chem. 2008; 283(50):35258-64. PMC: 2596411. DOI: 10.1074/jbc.M806900200. View

Taverna S, Li H, Ruthenburg A, Allis C, Patel D . How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers. Nat Struct Mol Biol. 2007; 14(11):1025-1040. PMC: 4691843. DOI: 10.1038/nsmb1338. View

Kurash J, Lei H, Shen Q, Marston W, Granda B, Fan H . Methylation of p53 by Set7/9 mediates p53 acetylation and activity in vivo. Mol Cell. 2008; 29(3):392-400. DOI: 10.1016/j.molcel.2007.12.025. View

Van Duyne R, Easley R, Wu W, Berro R, Pedati C, Klase Z . Lysine methylation of HIV-1 Tat regulates transcriptional activity of the viral LTR. Retrovirology. 2008; 5:40. PMC: 2412914. DOI: 10.1186/1742-4690-5-40. View

Patel A, Dharmarajan V, Cosgrove M . Structure of WDR5 bound to mixed lineage leukemia protein-1 peptide. J Biol Chem. 2008; 283(47):32158-61. DOI: 10.1074/jbc.C800164200. View

Southall S, Wong P, Odho Z, Roe S, Wilson J . Structural basis for the requirement of additional factors for MLL1 SET domain activity and recognition of epigenetic marks. Mol Cell. 2009; 33(2):181-91. DOI: 10.1016/j.molcel.2008.12.029. View

10.

Huang J, Dorsey J, Chuikov S, Zhang X, Jenuwein T, Reinberg D . G9a and Glp methylate lysine 373 in the tumor suppressor p53. J Biol Chem. 2010; 285(13):9636-9641. PMC: 2843213. DOI: 10.1074/jbc.M109.062588. View

11.

Li B, Carey M, Workman J . The role of chromatin during transcription. Cell. 2007; 128(4):707-19. DOI: 10.1016/j.cell.2007.01.015. View

12.

Kouzarides T . Chromatin modifications and their function. Cell. 2007; 128(4):693-705. DOI: 10.1016/j.cell.2007.02.005. View

13.

Masatsugu T, Yamamoto K . Multiple lysine methylation of PCAF by Set9 methyltransferase. Biochem Biophys Res Commun. 2009; 381(1):22-6. DOI: 10.1016/j.bbrc.2009.01.185. View

14.

Huang J, Berger S . The emerging field of dynamic lysine methylation of non-histone proteins. Curr Opin Genet Dev. 2008; 18(2):152-8. DOI: 10.1016/j.gde.2008.01.012. View

15.

Yang X, Huang B, Li M, Lamb A, Kelleher N, Chen L . Negative regulation of NF-kappaB action by Set9-mediated lysine methylation of the RelA subunit. EMBO J. 2009; 28(8):1055-66. PMC: 2683704. DOI: 10.1038/emboj.2009.55. View

16.

Demirci H, Gregory S, Dahlberg A, Jogl G . Multiple-site trimethylation of ribosomal protein L11 by the PrmA methyltransferase. Structure. 2008; 16(7):1059-66. PMC: 2684062. DOI: 10.1016/j.str.2008.03.016. View

17.

Patel A, Vought V, Dharmarajan V, Cosgrove M . A novel non-SET domain multi-subunit methyltransferase required for sequential nucleosomal histone H3 methylation by the mixed lineage leukemia protein-1 (MLL1) core complex. J Biol Chem. 2010; 286(5):3359-69. PMC: 3030342. DOI: 10.1074/jbc.M110.174524. View

18.

Porras-Yakushi T, Whitelegge J, Miranda T, Clarke S . A novel SET domain methyltransferase modifies ribosomal protein Rpl23ab in yeast. J Biol Chem. 2005; 280(41):34590-8. DOI: 10.1074/jbc.M507672200. View

19.

Xiao B, Jing C, Wilson J, Walker P, Vasisht N, Kelly G . Structure and catalytic mechanism of the human histone methyltransferase SET7/9. Nature. 2003; 421(6923):652-6. DOI: 10.1038/nature01378. View

20.

Porras-Yakushi T, Whitelegge J, Clarke S . Yeast ribosomal/cytochrome c SET domain methyltransferase subfamily: identification of Rpl23ab methylation sites and recognition motifs. J Biol Chem. 2007; 282(17):12368-76. DOI: 10.1074/jbc.M611896200. View