KDM1A

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Not to be confused with LSD or Lysergic acid diethylamide.
Lysine (K)-specific demethylase 1A
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols KDM1A ; AOF2; BHC110; KDM1; LSD1
External IDs OMIM609132 HomoloGene32240 IUPHAR: 2669 GeneCards: KDM1A Gene
Orthologs
Species Human Mouse
Entrez 23028 99982
Ensembl ENSG00000004487 ENSMUSG00000036940
UniProt O60341 Q6ZQ88
RefSeq (mRNA) NM_001009999 NM_133872
RefSeq (protein) NP_001009999 NP_598633
Location (UCSC) Chr 1:
23.35 – 23.41 Mb
Chr 4:
136.55 – 136.6 Mb
PubMed search [1] [2]

Lysine-specific histone demethylase 1A (KDM1A) also known as lysine (K)-specific demethylase 1A (LSD1) is a protein in humans that is encoded by the KDM1A gene.[1] LSD1 is a flavin-dependent monoamine oxidase, which can demethylate mono- and di-methylated lysines, specifically histone 3, lysines 4 and 9 (H3K4 and H3K9).[2] This enzyme can have roles critical in embryogenesis and tissue-specific differentiation, as well as oocyte growth.[3] KDM1A was the first demethylase to be discovered and thus it has been studied most extensively.[4]

Structure[edit]

This gene encodes a nuclear protein containing a SWIRM domain, a FAD-binding motif, and an amine oxidase domain. This protein is a component of several histone deacetylase complexes, though it silences genes by functioning as a histone demethylase.

Function[edit]

LSD1 (lysine-specific demethylase 1), also known as KDM1, is the first of several protein lysine demethylases discovered. Through a FAD-dependent oxidative reaction, LSD1 speficially removes histone H3K4me2 to H3K4me1 or H3K4me0. When forming a complex with androgen receptor (and possibly other nuclear hormone receptors), LSD1 changes its substrates to H3K9me2. It's now known LSD1 complex mediates a coordinated histone modification switch through enzymatic activities as well as histone modification readers in the complex.

Interactions[edit]

KDM1A has many different binding partners, which may be necessary for its demethylation activity.[5]

Clinical significance[edit]

Deletion of the gene for KDM1A can have effects on the growth and differentiation of embryonic stem cells[6] and can lead to embryonic lethality in knockout mice, who do not produce the KDM1A gene product[7][8] KDM1A is also thought to play a role in cancer, as poorer outcomes can be correlated with higher expression of this gene.[9][10] Therefore, the inhibition of KDM1A may be a possible treatment for cancer.[11][12][13][14]

Mutations[edit]

De novo mutations to KDM1A have been reported in two patients, both with severe developmental delays believed to be attributable in part to the mutations. Both mutations were missense substitutions.[15][16] One of the affected families has created a public website in order to identify further cases. [17]

See also[edit]

References[edit]

  1. ^ "Entrez Gene: Lysine (K)-specific demethylase 1A". 
  2. ^ Rudolph T, Beuch S, Reuter G (Aug 2013). "Lysine-specific histone demethylase LSD1 and the dynamic control of chromatin". (review). Biological Chemistry 394 (8): 1019–28. doi:10.1515/hsz-2013-0119. PMID 23612539. 
  3. ^ Pedersen MT, Helin K (Nov 2010). "Histone demethylases in development and disease". (review). Trends in Cell Biology 20 (11): 662–71. doi:10.1016/j.tcb.2010.08.011. PMID 20863703. 
  4. ^ Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA et al. (Dec 2004). "Histone demethylation mediated by the nuclear amine oxidase homolog LSD1". Cell 119 (7): 941–53. doi:10.1016/j.cell.2004.12.012. PMID 15620353. 
  5. ^ Wang Y, Zhang H, Chen Y, Sun Y, Yang F, Yu W et al. (Aug 2009). "LSD1 is a subunit of the NuRD complex and targets the metastasis programs in breast cancer". Cell 138 (4): 660–72. doi:10.1016/j.cell.2009.05.050. PMID 19703393. 
  6. ^ Amente S, Lania L, Majello B (Oct 2013). "The histone LSD1 demethylase in stemness and cancer transcription programs". Biochimica Et Biophysica Acta 1829 (10): 981–6. doi:10.1016/j.bbagrm.2013.05.002. PMID 23684752. 
  7. ^ Wang J, Hevi S, Kurash JK, Lei H, Gay F, Bajko J et al. (Jan 2009). "The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylation". Nature Genetics 41 (1): 125–9. doi:10.1038/ng.268. PMID 19098913. 
  8. ^ Wang J, Scully K, Zhu X, Cai L, Zhang J, Prefontaine GG et al. (Apr 2007). "Opposing LSD1 complexes function in developmental gene activation and repression programmes". Nature 446 (7138): 882–7. doi:10.1038/nature05671. PMID 17392792. 
  9. ^ Kahl P, Gullotti L, Heukamp LC, Wolf S, Friedrichs N, Vorreuther R et al. (Dec 2006). "Androgen receptor coactivators lysine-specific histone demethylase 1 and four and a half LIM domain protein 2 predict risk of prostate cancer recurrence". Cancer Research 66 (23): 11341–7. doi:10.1158/0008-5472.CAN-06-1570. PMID 17145880. 
  10. ^ Lim S, Janzer A, Becker A, Zimmer A, Schüle R, Buettner R et al. (Mar 2010). "Lysine-specific demethylase 1 (LSD1) is highly expressed in ER-negative breast cancers and a biomarker predicting aggressive biology". Carcinogenesis 31 (3): 512–20. doi:10.1093/carcin/bgp324. PMID 20042638. 
  11. ^ Stavropoulos P, Hoelz A (Jun 2007). "Lysine-specific demethylase 1 as a potential therapeutic target". (review). Expert Opinion on Therapeutic Targets 11 (6): 809–20. doi:10.1517/14728222.11.6.809. PMID 17504018. 
  12. ^ Chen Y, Jie W, Yan W, Zhou K, Xiao Y. "Lysine-specific histone demethylase 1 (LSD1): A potential molecular target for tumor therapy". (review). Critical Reviews in Eukaryotic Gene Expression 22 (1): 53–9. PMID 22339659. 
  13. ^ Crea F, Sun L, Mai A, Chiang YT, Farrar WL, Danesi R et al. "The emerging role of histone lysine demethylases in prostate cancer". (review). Molecular Cancer 11: 52. doi:10.1186/1476-4598-11-52. PMID 22867098. 
  14. ^ Lynch JT, Harris WJ, Somervaille TC (Dec 2012). "LSD1 inhibition: a therapeutic strategy in cancer?". (review). Expert Opinion on Therapeutic Targets 16 (12): 1239–49. doi:10.1517/14728222.2012.722206. PMID 22957941. 
  15. ^ Tunovic S, Barkovich J, Sherr EH, Slavotinek AM (Jul 2014). "De novo ANKRD11 and KDM1A gene mutations in a male with features of KBG syndrome and Kabuki syndrome". American Journal of Medical Genetics. Part A 164A (7): 1744–9. doi:10.1002/ajmg.a.36450. PMID 24838796. 
  16. ^ Rauch A, Wieczorek D, Graf E, Wieland T, Endele S, Schwarzmayr T et al. (Nov 2012). "Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study". Lancet 380 (9854): 1674–82. doi:10.1016/S0140-6736(12)61480-9. PMID 23020937. 
  17. ^ "Milo's Journey". 

External links[edit]

This article incorporates text from the United States National Library of Medicine, which is in the public domain.