KDM2A explained

Lysine-specific demethylase 2A (KDM2A) also known as F-box and leucine-rich repeat protein 11 (FBXL11) is an enzyme that in humans is encoded by the KDM2A gene.^{[1] [2] [3]} KDM2A is a member of the superfamily of alpha-ketoglutarate-dependent hydroxylases, which are non-haem iron-containing proteins.

Function

This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbls class and, in addition to an F-box, contains at least 6 highly degenerated leucine-rich repeats.^[3]

FBXL11/KDM2A is a histone H3 lysine 36 demethylase enzyme. The enzymatic activity of FBXL11/KDM2A relies on a conserved JmjC domain in the N-terminus of the protein that co-ordinates iron and alphaketoglutarate to catalyze demethylation via a hydroxylation based mechanism.^[4] It has recently been demonstrated that a ZF-CxxC DNA binding domain within FBXL11/KDM2A has the capacity to interact with non-methylated DNA and this domain targets FBXL11/KDM2A to CpG island regions of the genome where it specifically removes histone H3 lysine 36 methylation.^[5] This mechanism acts to create a chromatin environment at CpG islands that highlights these regulatory elements and differentiates them from non-regulatory regions in large complex mammalian genomes. In a study in mouse hepatocytes, this gene was shown to regulate hepatic gluconeogenesis.^[6]

Further reading

• Nakajima D, Okazaki N, Yamakawa H, Kikuno R, Ohara O, Nagase T . Construction of expression-ready cDNA clones for KIAA genes: manual curation of 330 KIAA cDNA clones. . DNA Res. . 9 . 3 . 99–106 . 2003 . 12168954 . 10.1093/dnares/9.3.99 . free .
• Cenciarelli C, Chiaur DS, Guardavaccaro D, Parks W, Vidal M, Pagano M . Identification of a family of human F-box proteins. . Curr. Biol. . 9 . 20 . 1177–9 . 1999 . 10531035 . 10.1016/S0960-9822(00)80020-2 . 7467493 . free . 1999CBio....9.1177C .
• Ilyin GP, Rialland M, Pigeon C, Guguen-Guillouzo C . cDNA cloning and expression analysis of new members of the mammalian F-box protein family. . Genomics . 67 . 1 . 40–7 . 2001 . 10945468 . 10.1006/geno.2000.6211 .
• Hattori A, Okumura K, Nagase T, Kikuno R, Hirosawa M, Ohara O . Characterization of long cDNA clones from human adult spleen. . DNA Res. . 7 . 6 . 357–66 . 2001 . 11214971 . 10.1093/dnares/7.6.357 . free .
• Watanabe N, Arai H, Nishihara Y, Taniguchi M, Watanabe N, Hunter T, Osada H . M-phase kinases induce phospho-dependent ubiquitination of somatic Wee1 by SCFbeta-TrCP. . Proc. Natl. Acad. Sci. U.S.A. . 101 . 13 . 4419–24 . 2004 . 15070733 . 384762 . 10.1073/pnas.0307700101 . 2004PNAS..101.4419W . free .
• Colland F, Jacq X, Trouplin V, Mougin C, Groizeleau C, Hamburger A, Meil A, Wojcik J, Legrain P, Gauthier JM . Functional proteomics mapping of a human signaling pathway. . Genome Res. . 14 . 7 . 1324–32 . 2004 . 15231748 . 442148 . 10.1101/gr.2334104 .
• Andersen JS, Lam YW, Leung AK, Ong SE, Lyon CE, Lamond AI, Mann M . Nucleolar proteome dynamics. . Nature . 433 . 7021 . 77–83 . 2005 . 15635413 . 10.1038/nature03207 . 2005Natur.433...77A . 4344740 .
• Tsukada Y, Fang J, Erdjument-Bromage H, Warren ME, Borchers CH, Tempst P, Zhang Y . Histone demethylation by a family of JmjC domain-containing proteins. . Nature . 439 . 7078 . 811–6 . 2006 . 16362057 . 10.1038/nature04433 . 2006Natur.439..811T . 4415889 .
• Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M . Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. . Cell . 127 . 3 . 635–48 . 2006 . 17081983 . 10.1016/j.cell.2006.09.026 . 7827573 . free .

Notes and References

1. Nagase T, Ishikawa K, Suyama M, Kikuno R, Hirosawa M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O . Prediction of the coding sequences of unidentified human genes. XIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro . DNA Res . 6 . 1 . 63–70 . Jul 1999 . 10231032 . 10.1093/dnares/6.1.63 . free .
2. Winston JT, Koepp DM, Zhu C, Elledge SJ, Harper JW . A family of mammalian F-box proteins . Curr Biol . 9 . 20 . 1180–2 . Dec 1999 . 10531037 . 10.1016/S0960-9822(00)80021-4 . 14341845 . free . 1999CBio....9.1180W .
3. Web site: Entrez Gene: FBXL11 F-box and leucine-rich repeat protein 11.
4. Tsukada Y, Fang J, Erdjument-Bromage H, Warren ME, Borchers CH, Tempst P, Zhang Y . Histone demethylation by a family of JmjC domain-containing proteins . Nature . 439 . 7078 . 811–6 . February 2006 . 16362057 . 10.1038/nature04433 . 2006Natur.439..811T . 4415889 .
5. Blackledge NP, Zhou JC, Tolstorukov MY, Farcas AM, Park PJ, Klose RJ . CpG islands recruit a histone H3 lysine 36 demethylase . Molecular Cell . 38 . 2 . 179–90 . Apr 2010 . 20417597 . 10.1016/j.molcel.2010.04.009 . 3098377.
6. Pan D, Mao C, Zou T, Yao AY, Cooper MP, Boyartchuk V, Wang YX . The Histone Demethylase Jhdm1a Regulates Hepatic Gluconeogenesis . PLOS Genetics . 8 . 6 . e1002761 . 22719268 . 10.1371/journal.pgen.1002761 . 3375226 . 2012 . free .