KDM5A explained

Lysine-specific demethylase 5A is an enzyme that in humans is encoded by the KDM5A gene.^{[1] [2]}

Function

The protein encoded by this gene is a ubiquitously expressed nuclear protein. It binds directly, with several other proteins, to retinoblastoma protein which regulates cell proliferation. It was formerly known as Retinoblastoma Binding Protein 2 (RBP2). This protein also interacts with rhombotin-2 which functions distinctly in erythropoiesis and in T-cell leukemogenesis. Rhombotin-2 is thought to either directly affect the activity of the encoded protein or may indirectly modulate the functions of the retinoblastoma protein by binding to this protein. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.^[2]

The Drosophila homolog, LID, was found to be an H3K4 histone demethylase that binds to c-Myc.^[3] It was recently renamed to Lysine Demethylase 5 (KDM5).

Enzymatically can be designated as a trimethyllysine dioxygenase, which is a member of the alpha-ketoglutarate-dependent hydroxylase superfamily .

Interactions

JARID1A has been shown to interact with Estrogen receptor alpha,^[4] LMO2^[5] and Retinoblastoma protein.^{[4] [6]}

JARID1A is a major component of the circadian clock, the upregulation of which at the end of the sleep phase blocks HDAC1 activity. Blocking HDAC1 activity results in an upregulation of CLOCK and BMAL1 and consequent upregulation of PER proteins. The PSF (polypyrimidine tract-binding protein-associated splicing factor) within the PER complex recruits SIN3A, a scaffold for assembly of transcriptional inhibitory complexes and rhythmically delivers histone deacetylases to the Per1 promoter, which repress Per1 transcription.^{[7] [8]}

Knockdown of JARID1A promoted osteogenic differentiation of human adipose-derived stromal cells in vitro and in vivo and resulted in marked increases of mRNA expression of osteogenesis-associated genes such as alkaline phosphatase (ALP), osteocalcin (OC), and osterix (OSX). RBP2 was shown to occupy the promoters of OSX and OC to maintain the level of the H3K4me3 mark by chromatin immunoprecipitation assays. RBP2 was also physically and functionally associated with RUNX2, an essential transcription factor that governed osteoblastic differentiation. RUNX2 knockdown impaired the repressive activity of RBP2 in osteogenic differentiation of human adipose-derived stromal cells.^[9]

Further reading

• Kim YW, Otterson GA, Kratzke RA, Coxon AB, Kaye FJ . Differential specificity for binding of retinoblastoma binding protein 2 to RB, p107, and TATA-binding protein . Molecular and Cellular Biology . 14 . 11 . 7256–64 . Nov 1994 . 7935440 . 359260 . 10.1128/mcb.14.11.7256.
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . Jan 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Fattaey AR, Helin K, Dembski MS, Dyson N, Harlow E, Vuocolo GA, Hanobik MG, Haskell KM, Oliff A, Defeo-Jones D . Characterization of the retinoblastoma binding proteins RBP1 and RBP2 . Oncogene . 8 . 11 . 3149–56 . Nov 1993 . 8414517 .
• Baens M, Aerssens J, van Zand K, Van den Berghe H, Marynen P . Isolation and regional assignment of human chromosome 12p cDNAs . Genomics . 29 . 1 . 44–52 . Sep 1995 . 8530100 . 10.1006/geno.1995.1213 .
• Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA . A "double adaptor" method for improved shotgun library construction . Analytical Biochemistry . 236 . 1 . 107–13 . Apr 1996 . 8619474 . 10.1006/abio.1996.0138 .
• Hillier LD, Lennon G, Becker M, Bonaldo MF, Chiapelli B, Chissoe S, Dietrich N, DuBuque T, Favello A, Gish W, Hawkins M, Hultman M, Kucaba T, Lacy M, Le M, Le N, Mardis E, Moore B, Morris M, Parsons J, Prange C, Rifkin L, Rohlfing T, Schellenberg K, Bento Soares M, Tan F, Thierry-Meg J, Trevaskis E, Underwood K, Wohldman P, Waterston R, Wilson R, Marra M . Generation and analysis of 280,000 human expressed sequence tags . Genome Research . 6 . 9 . 807–28 . Sep 1996 . 8889549 . 10.1101/gr.6.9.807 . free .
• Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G, Gibbs RA . Large-scale concatenation cDNA sequencing . Genome Research . 7 . 4 . 353–8 . Apr 1997 . 9110174 . 139146 . 10.1101/gr.7.4.353 .
• Mao S, Neale GA, Goorha RM . T-cell oncogene rhombotin-2 interacts with retinoblastoma-binding protein 2 . Oncogene . 14 . 13 . 1531–9 . Apr 1997 . 9129143 . 10.1038/sj.onc.1200988 . free .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . Oct 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Chan SW, Hong W . Retinoblastoma-binding protein 2 (Rbp2) potentiates nuclear hormone receptor-mediated transcription . The Journal of Biological Chemistry . 276 . 30 . 28402–12 . Jul 2001 . 11358960 . 10.1074/jbc.M100313200 . free .
• Sandrock B, Egly JM . A yeast four-hybrid system identifies Cdk-activating kinase as a regulator of the XPD helicase, a subunit of transcription factor IIH . The Journal of Biological Chemistry . 276 . 38 . 35328–33 . Sep 2001 . 11445587 . 10.1074/jbc.M105570200 . free .
• Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, Cohn MA, Cantley LC, Gygi SP . Large-scale characterization of HeLa cell nuclear phosphoproteins . Proceedings of the National Academy of Sciences of the United States of America . 101 . 33 . 12130–5 . Aug 2004 . 15302935 . 514446 . 10.1073/pnas.0404720101 . 2004PNAS..10112130B . free .
• Benevolenskaya EV, Murray HL, Branton P, Young RA, Kaelin WG . Binding of pRB to the PHD protein RBP2 promotes cellular differentiation . Molecular Cell . 18 . 6 . 623–35 . Jun 2005 . 15949438 . 10.1016/j.molcel.2005.05.012 . free .
• Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, Yamamoto J, Sekine M, Tsuritani K, Wakaguri H, Ishii S, Sugiyama T, Saito K, Isono Y, Irie R, Kushida N, Yoneyama T, Otsuka R, Kanda K, Yokoi T, Kondo H, Wagatsuma M, Murakawa K, Ishida S, Ishibashi T, Takahashi-Fujii A, Tanase T, Nagai K, Kikuchi H, Nakai K, Isogai T, Sugano S . Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes . Genome Research . 16 . 1 . 55–65 . Jan 2006 . 16344560 . 1356129 . 10.1101/gr.4039406 .
• Tzschach A, Lenzner S, Moser B, Reinhardt R, Chelly J, Fryns JP, Kleefstra T, Raynaud M, Turner G, Ropers HH, Kuss A, Jensen LR . Novel JARID1C/SMCX mutations in patients with X-linked mental retardation . Human Mutation . 27 . 4 . 389 . Apr 2006 . 16541399 . 10.1002/humu.9420 . 25318561 . free .
• Roesch A, Becker B, Schneider-Brachert W, Hagen I, Landthaler M, Vogt T . Re-expression of the retinoblastoma-binding protein 2-homolog 1 reveals tumor-suppressive functions in highly metastatic melanoma cells . The Journal of Investigative Dermatology . 126 . 8 . 1850–9 . Aug 2006 . 16645588 . 10.1038/sj.jid.5700324 . free .
• 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 . Nov 2006 . 17081983 . 10.1016/j.cell.2006.09.026 . 7827573 . free .

Notes and References

1. Defeo-Jones D, Huang PS, Jones RE, Haskell KM, Vuocolo GA, Hanobik MG, Huber HE, Oliff A . Cloning of cDNAs for cellular proteins that bind to the retinoblastoma gene product . Nature . 352 . 6332 . 251–4 . Jul 1991 . 1857421 . 10.1038/352251a0 . 1991Natur.352..251D . 4357523 .
2. Web site: Entrez Gene: JARID1A jumonji, AT rich interactive domain 1A.
3. Secombe J, Li L, Carlos L, Eisenman RN . The Trithorax group protein Lid is a trimethyl histone H3K4 demethylase required for dMyc-induced cell growth . Genes & Development . 21 . 5 . 537–51 . Mar 2007 . 17311883 . 1820896 . 10.1101/gad.1523007 .
4. Chan SW, Hong W . Retinoblastoma-binding protein 2 (Rbp2) potentiates nuclear hormone receptor-mediated transcription . The Journal of Biological Chemistry . 276 . 30 . 28402–12 . Jul 2001 . 11358960 . 10.1074/jbc.M100313200 . free .
5. Mao S, Neale GA, Goorha RM . T-cell oncogene rhombotin-2 interacts with retinoblastoma-binding protein 2 . Oncogene . 14 . 13 . 1531–9 . Apr 1997 . 9129143 . 10.1038/sj.onc.1200988 . free .
6. Kim YW, Otterson GA, Kratzke RA, Coxon AB, Kaye FJ . Differential specificity for binding of retinoblastoma binding protein 2 to RB, p107, and TATA-binding protein . Molecular and Cellular Biology . 14 . 11 . 7256–64 . Nov 1994 . 7935440 . 359260 . 10.1128/mcb.14.11.7256.
7. DiTacchio L, Le HD, Vollmers C, Hatori M, Witcher M, Secombe J, Panda S . Histone lysine demethylase JARID1a activates CLOCK-BMAL1 and influences the circadian clock . Science . 333 . 6051 . 1881–5 . 2011 . 21960634 . 3204309 . 10.1126/science.1206022 . 2011Sci...333.1881D .
8. Duong HA, Robles MS, Knutti D, Weitz CJ . A molecular mechanism for circadian clock negative feedback . Science . 332 . 6036 . 1436–9 . 2011 . 21680841 . 3859310 . 10.1126/science.1196766 . 2011Sci...332.1436D .
9. Ge W, Shi L, Zhou Y, Liu Y, Ma GE, Jiang Y, Xu Y, Zhang X, Feng H . Inhibition of osteogenic differentiation of human adipose-derived stromal cells by retinoblastoma binding protein 2 repression of RUNX2-activated transcription . Stem Cells . 29 . 7 . 1112–25 . 2011 . 21604327 . 10.1002/stem.663 . 41977627 . free .