SETD6 explained

SET domain containing 6 is a protein in humans that is encoded by the SETD6 gene.^[1]

SETD6 monomethylates the RelA subunit of nuclear factor kappa B (NF-κB). RelA mono-methylation at lysine 310 (RelAK310me1) leads to the constitutive repression of RelA target genes by recruiting the PKMT G9a-like protein (GLP), which catalyzes H3K9me2 and leads to chromatin silencing and gene repression. In response to stimulation with TNFa and lipopolysaccharide, phosphorylation of RelA at serine 311 (RelAS311ph) by PKCzeta physically blocks the interaction between GLP and RelAK310me1, leading to transcription activation.^[2]

PAK4 Methylation by SETD6 Promotes the Activation of the Wnt/β-Catenin Pathway. SETD6 binds and methylates PAK4 both in vitro and in cells at chromatin. Depletion of SETD6 in various cell lines leads to a dramatic reduction in the expression of Wnt/�-catenin target genes.^[3]

SETD6 binds to but does not methylate DJ1. Under basal conditions, SETD6 and DJ1 associate with chromatin which inhibits DJ1 to activate Nrf2 transcription activity. In response to oxidative stress, SETD6 mRNA and protein levels are dramatically reduced.^[4]

SETD6 specifically binds and methylates PLK1 during mitosis at K209 and K413. Depletion of SETD6, as well as the double substitution of the lysine residues (K209/413R), leads to elevation in PLK1 catalytic activity, leading to the acceleration of the different mitotic steps, ending with early cytokinesis.^[5]

Further reading

• Weil LE, Shmidov Y, Kublanovsky M, Morgenstern D, Feldman M, Bitton R, Levy D . Oligomerization and Auto-methylation of the Human Lysine Methyltransferase SETD6 . Journal of Molecular Biology . 430 . 21 . 4359–4368 . October 2018 . 30189201 . 10.1016/j.jmb.2018.08.028 . 52167348 .
• Kublanovsky M, Aharoni A, Levy D . Enhanced PKMT-substrate recognition through non active-site interactions . Biochemical and Biophysical Research Communications . 501 . 4 . 1029–1033 . July 2018 . 29778536 . 10.1016/j.bbrc.2018.05.103 . 205956659 .
• Feldman M, Levy D . Peptide inhibition of the SETD6 methyltransferase catalytic activity . Oncotarget . 9 . 4 . 4875–4885 . January 2018 . 29435148 . 5797019 . 10.18632/oncotarget.23591 .
• Martín-Morales L, Feldman M, Vershinin Z, Garre P, Caldés T, Levy D . SETD6 dominant negative mutation in familial colorectal cancer type X . Human Molecular Genetics . 26 . 22 . 4481–4493 . November 2017 . 28973356 . 10.1093/hmg/ddx336 . free .
• Chang Y, Levy D, Horton JR, Peng J, Zhang X, Gozani O, Cheng X . Structural basis of SETD6-mediated regulation of the NF-kB network via methyl-lysine signaling . Nucleic Acids Research . 39 . 15 . 6380–9 . August 2011 . 21515635 . 3159447 . 10.1093/nar/gkr256 .
• Levy D, Liu CL, Yang Z, Newman AM, Alizadeh AA, Utz PJ, Gozani O . A proteomic approach for the identification of novel lysine methyltransferase substrates . Epigenetics & Chromatin . 4 . 19 . October 2011 . 22024134 . 3212905 . 10.1186/1756-8935-4-19 . free .

Notes and References

1. Web site: Entrez Gene: SET domain containing 6. 2017-11-01. 2010-12-05. https://web.archive.org/web/20101205081110/http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene. live.
2. Levy D, Kuo AJ, Chang Y, Schaefer U, Kitson C, Cheung P, Espejo A, Zee BM, Liu CL, Tangsombatvisit S, Tennen RI, Kuo AY, Tanjing S, Cheung R, Chua KF, Utz PJ, Shi X, Prinjha RK, Lee K, Garcia BA, Bedford MT, Tarakhovsky A, Cheng X, Gozani O . Lysine methylation of the NF-κB subunit RelA by SETD6 couples activity of the histone methyltransferase GLP at chromatin to tonic repression of NF-κB signaling . Nature Immunology . 12 . 1 . 29–36 . January 2011 . 21131967 . 3074206 . 10.1038/ni.1968 .
3. Vershinin Z, Feldman M, Chen A, Levy D . PAK4 Methylation by SETD6 Promotes the Activation of the Wnt/β-Catenin Pathway . The Journal of Biological Chemistry . 291 . 13 . 6786–95 . March 2016 . 26841865 . 4807267 . 10.1074/jbc.M115.697292 . free .
4. Chen A, Feldman M, Vershinin Z, Levy D . SETD6 is a negative regulator of oxidative stress response . Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms . 1859 . 2 . 420–7 . February 2016 . 26780326 . 10.1016/j.bbagrm.2016.01.003 .
5. Feldman M, Vershinin Z, Goliand I, Elia N, Levy D . The methyltransferase SETD6 regulates Mitotic progression through PLK1 methylation . Proceedings of the National Academy of Sciences of the United States of America . 116 . 4 . 1235–1240 . January 2019 . 30622182 . 6347700 . 10.1073/pnas.1804407116 . 2019PNAS..116.1235F . free .