title: 5-hydroxymethylcytosine and its potential roles in development and cancer.
abstract: Only a few years ago it was demonstrated that mammalian DNA contains oxidized forms of 5-methylcytosine (5mC). The base 5-hydroxymethylcytosine (5hmC) is the most abundant of these oxidation products and is referred to as the sixth DNA base. 5hmC is produced from 5mC in an enzymatic pathway involving three 5mC oxidases, Ten-eleven translocation (TET)1, TET2, and TET3. The biological role of 5hmC is still unclear. Current models propose that 5hmC is an intermediate base in an active or passive DNA demethylation process that operates during important reprogramming phases of mammalian development. Tumors originating in various human tissues have strongly depleted levels of 5hmC. Apparently, 5hmC cannot be maintained in proliferating cells. Furthermore, mutations in the TET2 gene are commonly observed in human myeloid malignancies. Since TET proteins and many lysine demethylases require 2-oxoglutarate as a cofactor, aberrations in cofactor biochemical pathways, including mutations in isocitrate dehydrogenase (IDH), may affect levels of 5hmC and 5mC in certain types of tumors, either directly or indirectly. We discuss current data and models of the function of 5hmC in general, with special emphasis on its role in mechanisms of development and cancer.
authors: Department of Cancer Biology, Beckman Research Institute, City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA. gpfeifer@coh.org.
authors: Gerd P
authors: GP
authors: Pfeifer
authors: Swati
authors: S
authors: Kadam
authors: Seung-Gi
authors: SG
authors: Jin
references: Nature. 2011 Sep 04;477(7366):606-10
references: 21892189
references: Cell Cycle. 2009 Jun 1;8(11):1698-710
references: 19411852
references: N Engl J Med. 2012 Jan 5;366(1):95-6
references: 22216861
references: Nucleic Acids Res. 2012 Nov 1;40(20):10203-14
references: 22962365
references: J Biol Chem. 2012 Sep 28;287(40):33116-21
references: 22898819
references: Proc Natl Acad Sci U S A. 2011 Aug 30;108(35):14566-71
references: 21873190
references: Cancer Res. 2002 Jul 15;62(14):4075-80
references: 12124344
references: Genes Dev. 2011 Dec 1;25(23):2436-52
references: 22156206
references: Blood. 2009 Jul 2;114(1):144-7
references: 19420352
references: Biochem J. 1972 Feb;126(4):781-90
references: 4538516
references: Cell. 2012 Dec 21;151(7):1417-30
references: 23260135
references: J Gen Physiol. 1953 Jul;36(6):777-89
references: 13069681
references: PLoS One. 2011;6(6):e21306
references: 21731699
references: Science. 2009 May 15;324(5929):929-30
references: 19372393
references: Nat Protoc. 2012 Dec;7(12):2159-70
references: 23196972
references: Cell. 2012 Dec 7;151(6):1200-13
references: 23217707
references: Cancer Cell. 2010 May 18;17(5):510-22
references: 20399149
references: Proc Natl Acad Sci U S A. 1999 Jul 20;96(15):8681-6
references: 10411935
references: Nature. 2010 Feb 25;463(7284):1101-5
references: 20098412
references: Nat Rev Cancer. 2012 Sep;12(9):599-612
references: 22898539
references: Science. 2011 Sep 2;333(6047):1303-7
references: 21817016
references: Blood. 2009 Jun 18;113(25):6403-10
references: 19372255
references: Nature. 2000 Feb 3;403(6769):501-2
references: 10676950
references: Nature. 2012 Jun 03;486(7403):415-9
references: 22722204
references: Oncogene. 2013 Jan 31;32(5):663-9
references: 22391558
references: Curr Biol. 2000 Apr 20;10(8):475-8
references: 10801417
references: Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14183-7
references: 11121024
references: Cancer Sci. 2012 Apr;103(4):670-6
references: 22320381
references: Trends Biochem Sci. 2006 Feb;31(2):89-97
references: 16403636
references: Nature. 2010 Aug 26;466(7310):1129-33
references: 20639862
references: Blood. 2011 Oct 27;118(17):4509-18
references: 21803851
references: Science. 2013 Jan 25;339(6118):448-52
references: 23223451
references: Nature. 2010 Dec 9;468(7325):839-43
references: 21057493
references: Nature. 2009 Dec 10;462(7274):739-44
references: 19935646
references: J Biol Chem. 2001 Nov 9;276(45):41991-7
references: 11526119
references: Cell. 2013 Feb 28;152(5):1146-59
references: 23434322
references: J Cell Sci. 2009 Aug 15;122(Pt 16):2787-91
references: 19657014
references: Genome Res. 2012 Mar;22(3):467-77
references: 22106369
references: Nat Genet. 1999 Oct;23(2):185-8
references: 10508514
references: Nat Neurosci. 2011 Oct 30;14(12):1607-16
references: 22037496
references: Cancer Cell. 2010 Dec 14;18(6):553-67
references: 21130701
references: Cell Cycle. 2011 Aug 15;10(16):2662-8
references: 21811096
references: Cell. 2012 Sep 14;150(6):1135-46
references: 22980977
references: Cancer Res. 2011 Dec 15;71(24):7360-5
references: 22052461
references: Mol Cell. 2012 Dec 28;48(6):849-62
references: 23219530
references: J Mol Evol. 1976 May 26;7(4):325-9
references: 933178
references: Science. 2009 May 15;324(5929):930-5
references: 19372391
references: Cell. 2011 Jul 8;146(1):67-79
references: 21722948
references: Nucleic Acids Res. 2004 Aug 09;32(14):4100-8
references: 15302911
references: Proc Natl Acad Sci U S A. 2011 Mar 1;108(9):3642-7
references: 21321204
references: Cell Rep. 2013 Feb 21;3(2):291-300
references: 23403289
references: Nat Commun. 2011;2:241
references: 21407207
references: J Am Chem Soc. 2011 Jan 26;133(3):486-92
references: 21155562
references: Cancer Cell. 2011 Jul 12;20(1):11-24
references: 21723200
references: Angew Chem Int Ed Engl. 2012 Jun 25;51(26):6516-20
references: 22644704
references: Oncotarget. 2011 Aug;2(8):627-37
references: 21896958
references: Trends Genet. 2012 Apr;28(4):164-74
references: 22386917
references: Dev Cell. 2013 Feb 11;24(3):310-23
references: 23352810
references: Int J Cancer. 2012 Oct 1;131(7):1577-90
references: 22234893
references: Nat Rev Cancer. 2010 Jan;10(1):23-36
references: 20029422
references: Nat Biotechnol. 2011 Jan;29(1):68-72
references: 21151123
references: Science. 2010 Oct 29;330(6004):622-7
references: 21030646
references: Nucleic Acids Res. 2010 Jun;38(11):e125
references: 20371518
references: Science. 2011 Oct 14;334(6053):194
references: 21940858
references: Nucleic Acids Res. 2012 Jun;40(11):4841-9
references: 22362737
references: Blood. 2009 Oct 8;114(15):3285-91
references: 19666869
references: Nature. 2012 Feb 15;483(7390):479-83
references: 22343889
references: Angew Chem Int Ed Engl. 2010 Jul 19;49(31):5375-7
references: 20583021
references: Cell. 2011 Dec 23;147(7):1498-510
references: 22196727
references: Cancer Cell. 2011 Jul 12;20(1):25-38
references: 21723201
references: Nature. 2012 Aug 30;488(7413):656-9
references: 22763442
references: Cancer Cell. 2011 Jan 18;19(1):17-30
references: 21251613
references: Nature. 2013 May 2;497(7447):122-6
references: 23563267
references: Nucleic Acids Res. 2011 Jul;39(12):5015-24
references: 21378125
references: Cancer Res. 2007 Feb 1;67(3):946-50
references: 17283125
references: Nat Genet. 2009 Jul;41(7):838-42
references: 19483684
references: Oncogene. 2010 Dec 9;29(49):6409-17
references: 20972461
references: Science. 2010 Jul 2;329(5987):78-82
references: 20595612
references: N Engl J Med. 2009 Feb 19;360(8):765-73
references: 19228619
references: PLoS One. 2010 Dec 23;5(12):e15367
references: 21203455
references: Science. 2011 Sep 2;333(6047):1300-3
references: 21778364
references: N Engl J Med. 2009 May 28;360(22):2289-301
references: 19474426
references: Nature. 2011 May 19;473(7347):398-402
references: 21460836
references: J Mol Cell Biol. 2012 Dec;4(6):427-9
references: 22750790
references: Nature. 2011 May 19;473(7347):343-8
references: 21490601
references: EMBO J. 2013 Feb 6;32(3):340-53
references: 23241950
references: EMBO J. 2013 Feb 6;32(3):318-21
references: 23299938
references: Anal Chem. 2012 Sep 4;84(17):7336-42
references: 22882125
references: PLoS One. 2012;7(2):e31605
references: 22328940