title: Human APOBEC3A isoforms translocate to the nucleus and induce DNA double strand breaks leading to cell stress and death.
abstract: Human APOBEC3 enzymes deaminate single stranded DNA. At least five can deaminate mitochondrial DNA in the cytoplasm, while three can deaminate viral DNA in the nucleus. However, only one, APOBEC3A, can hypermutate genomic DNA. We analysed the distribution and function of the two APOBEC3A isoforms p1 and p2 in transfected cell lines. Both can translocate to the nucleus and hypermutate CMYC DNA and induce DNA double strand breaks as visualized by the detection of ©H2AX or Chk2. APOBEC3A induced G1 phase cell cycle arrest and triggered several members of the intrinsic apoptosis pathway. Activation of purified human CD4+ T lymphocytes with PHA, IL2 and interferon α resulted in C->T hypermutation of genomic DNA and double stranded breaks suggesting a role for APOBEC3A in pro-inflammatory conditions. As chronic inflammation underlies many diseases including numerous cancers, it is possible that APOBEC3A induction may generate many of the lesions typical of a cancer genome.
authors: Molecular Retrovirology Unit, Institut Pasteur, Paris, France.
authors: Bianka
authors: B
authors: Mussil
authors: Rodolphe
authors: R
authors: Suspène
authors: Marie-Ming
authors: MM
authors: Aynaud
authors: Anne
authors: A
authors: Gauvrit
authors: Jean-Pierre
authors: JP
authors: Vartanian
authors: Simon
authors: S
authors: Wain-Hobson
mesh_terms: D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D059447:Cell Cycle Checkpoints; D016923:Cell Death; D002467:Cell Nucleus / Q000378:metabolism*; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D017393:RNA Editing / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D013312:Stress, Physiological; D051981:Uracil-DNA Glycosidase / Q000378:metabolism; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: C468783:H2AX protein, human; D006657:Histones; D020033:Protein Isoforms; D011506:Proteins; D051981:Uracil-DNA Glycosidase; D000098830:AICDA (Activation-Induced Cytidine Deaminase); C121399:APOBEC3A protein, human; D003564:Cytidine Deaminase
references: Nature. 2008 Feb 14;451(7180):841-5
references: 18273020
references: Biochem Pharmacol. 2003 Oct 15;66(8):1547-54
references: 14555233
references: DNA Repair (Amst). 2004 Oct 5;3(10):1323-34
references: 15336627
references: PLoS Pathog. 2011 Sep;7(9):e1002221
references: 21966267
references: Mutat Res. 2005 Sep 4;577(1-2):252-9
references: 15916783
references: J Virol. 2011 Aug;85(15):7594-602
references: 21632763
references: Cancer Res. 2000 Nov 1;60(21):5934-6
references: 11085506
references: Nature. 2002 Aug 8;418(6898):646-50
references: 12167863
references: Nat Cell Biol. 2002 Dec;4(12):993-7
references: 12447390
references: Hum Mol Genet. 2013 Mar 15;22(6):1262-9
references: 23213177
references: Nat Rev Cancer. 2008 Jul;8(7):512-22
references: 18574463
references: Nat Rev Cancer. 2008 Dec;8(12):957-67
references: 19005492
references: J Virol. 2008 Jul;82(13):6585-90
references: 18434399
references: Proc Natl Acad Sci U S A. 2002 Feb 5;99(3):1509-14
references: 11805288
references: Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):4858-63
references: 21368204
references: Free Radic Biol Med. 2008 Nov 1;45(9):1352-9
references: 18775489
references: Sci Rep. 2012;2:806
references: 23150777
references: Cell. 2004 Aug 20;118(4):431-8
references: 15315756
references: Trends Immunol. 2009 Apr;30(4):173-81
references: 19303358
references: Nat Rev Mol Cell Biol. 2000 Dec;1(3):179-86
references: 11252893
references: PLoS One. 2013 Jun 20;8(6):e63461
references: 23840298
references: PLoS One. 2009;4(1):e4277
references: 19169351
references: Int J Radiat Biol. 2006 Feb;82(2):111-8
references: 16546909
references: Mech Ageing Dev. 2005 Jun-Jul;126(6-7):621-8
references: 15888314
references: Biochem Cell Biol. 2007 Dec;85(6):663-74
references: 18059525
references: Cell Cycle. 2006 Dec;5(24):2909-13
references: 17172873
references: J Interferon Cytokine Res. 2009 Sep;29(9):569-80
references: 19694548
references: J Biol Chem. 2012 Nov 9;287(46):39182-92
references: 22977230
references: Mech Ageing Dev. 2008 Jul-Aug;129(7-8):483-91
references: 18455751
references: Nat Genet. 2001 Mar;27(3):247-54
references: 11242102
references: Ann Clin Lab Sci. 1997 Jul-Aug;27(4):260-75
references: 9210971
references: Blood. 1994 Sep 1;84(5):1415-20
references: 8068938
references: Cell. 2012 May 25;149(5):979-93
references: 22608084
references: PLoS Pathog. 2010 May 27;6(5):e1000928
references: 20523896
references: Nature. 1994 Sep 22;371(6495):346-7
references: 8090205
references: Nature. 2002 Jul 4;418(6893):99-103
references: 12097915
references: Radiat Res. 2004 May;161(5):517-27
references: 15161372
references: J Gen Virol. 2005 Jan;86(Pt 1):125-129
references: 15604439
references: Mol Cell Biol. 1992 Nov;12(11):5041-9
references: 1406679
references: Biochem J. 1997 Aug 15;326 ( Pt 1):1-16
references: 9337844
references: Nat Cell Biol. 2000 Oct;2(10):762-5
references: 11025670
references: Adv Immunol. 2007;94:245-73
references: 17560277
references: Nat Rev Immunol. 2004 Nov;4(11):868-77
references: 15516966
references: DNA Repair (Amst). 2007 Apr 1;6(4):544-59
references: 17112792
references: EMBO Rep. 2011 May;12(5):444-50
references: 21460793
references: J Virol. 2009 Apr;83(8):3486-95
references: 19153238
references: Mol Biol Evol. 2005 Feb;22(2):367-77
references: 15496550
references: Nature. 2003 Jul 3;424(6944):94-8
references: 12808465
references: DNA Repair (Amst). 2006 Aug 13;5(8):935-46
references: 16814620
references: Proc Natl Acad Sci U S A. 2005 Jun 7;102(23):8321-6
references: 15919829
references: Nucleic Acids Res. 2007;35(22):7466-74
references: 17913742
references: Cell. 2008 Dec 12;135(6):1028-38
references: 19070574
references: J Invest Dermatol. 2005 Apr;124(4):807-17
references: 15816840
references: Folia Histochem Cytobiol. 2007;45(4):279-90
references: 18165167
references: Nat Rev Mol Cell Biol. 2007 Sep;8(9):729-40
references: 17667954
references: J Virol. 2009 Sep;83(18):9474-85
references: 19587057
references: PLoS One. 2012;7(1):e30036
references: 22272271
references: Nat Immunol. 2009 Nov;10(11):1147-53
references: 19841648
references: Aging Cell. 2008 Jan;7(1):89-100
references: 18005250
references: Biochem Biophys Res Commun. 1998 Jul 9;248(1):18-21
references: 9675078
references: Cell Cycle. 2007 Feb 1;6(3):371-6
references: 17297310
references: J Virol. 2012 Jun;86(11):6097-108
references: 22457529
references: Acta Biochim Biophys Sin (Shanghai). 2010 Jul;42(7):440-9
references: 20705582
references: Cell. 2011 Jan 7;144(1):27-40
references: 21215367
references: Annu Rev Biochem. 2007;76:1-22
references: 17328676
references: Curr Biol. 2004 Aug 10;14(15):1392-6
references: 15296758
references: J Biol Chem. 2010 Sep 3;285(36):27753-66
references: 20615867
references: Arch Pathol Lab Med. 1999 Oct;123(10):921-7
references: 10506445
references: PLoS One. 2012;7(5):e38190
references: 22666481
references: Nature. 2009 Apr 9;458(7239):719-24
references: 19360079
references: J Virol. 2006 Jan;80(2):605-14
references: 16378963
references: Nature. 1992 Mar 26;356(6367):356-8
references: 1549180
references: Biochem Biophys Res Commun. 2006 Mar 10;341(2):314-9
references: 16426578
references: Trends Genet. 2008 Feb;24(2):77-85
references: 18192065
references: Curr Biol. 2004 Aug 10;14(15):1385-91
references: 15296757
references: Neurobiol Aging. 2006 Aug;27(8):1129-36
references: 16005114
references: J Gen Virol. 2008 Mar;89(Pt 3):722-730
references: 18272764
references: J Exp Med. 1995 Nov 1;182(5):1545-56
references: 7595224
references: DNA Repair (Amst). 2007 Feb 4;6(2):235-43
references: 17161027
references: Annu Rev Immunol. 2008;26:317-53
references: 18304004
references: J Biol Chem. 1998 Dec 11;273(50):33533-9
references: 9837934
references: Trends Microbiol. 2003 Dec;11(12):543-6
references: 14659685
references: Cell. 1995 Jun 2;81(5):801-9
references: 7774019
references: J Exp Med. 2003 May 5;197(9):1173-81
references: 12732658
references: Nat Struct Mol Biol. 2010 Feb;17(2):222-9
references: 20062055
references: Nature. 1998 Dec 17;396(6712):643-9
references: 9872311
references: Oncogene. 1999 Sep 20;18(38):5268-77
references: 10498879
references: Virus Res. 2005 Feb;107(2):117-27
references: 15649558
references: Science. 2003 May 16;300(5622):1112
references: 12750511
references: Hepatology. 2006 Jun;43(6):1364-74
references: 16729314
references: J Gen Virol. 2005 Sep;86(Pt 9):2489-2494
references: 16099907
references: Nature. 2013 Feb 21;494(7437):366-70
references: 23389445
references: Epigenetics Chromatin. 2008 Nov 03;1(1):6
references: 19014415
references: Genes Dev. 2000 Feb 1;14(3):278-88
references: 10673500
references: Science. 2008 Apr 11;320(5873):230-3
references: 18403710
references: Blood. 2007 Jul 1;110(1):393-400
references: 17371941
references: Virology. 2007 Oct 25;367(2):440-51
references: 17631933
references: Nature. 2006 Mar 2;440(7080):105-9
references: 16400328
references: J Biol Chem. 2012 Oct 5;287(41):34801-8
references: 22896697
references: Proc Natl Acad Sci U S A. 2000 Sep 12;97(19):10389-94
references: 10973490
references: J Bacteriol. 1988 Mar;170(3):1082-91
references: 2963806
references: Cell Rep. 2012 Nov 29;2(5):1438-47
references: 23159042
references: Nature. 1995 Jul 6;376(6535):37-43
references: 7596430
references: DNA Repair (Amst). 2004 Aug-Sep;3(8-9):889-900
references: 15279774
references: Elife. 2013 Apr 16;2:e00534
references: 23599896
references: Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6895-900
references: 11371613
references: Nucleic Acids Res. 2012 Oct;40(18):9206-17
references: 22798497
references: Genomics. 2002 Mar;79(3):285-96
references: 11863358
references: Nat Cell Biol. 2004 Feb;6(2):168-70
references: 14755273
references: Oncogene. 2006 Nov 9;25(53):7096-105
references: 16715126
references: Nature. 2003 Jul 3;424(6944):99-103
references: 12808466
references: Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):3035-40
references: 22315404
references: Cell Cycle. 2009 Aug;8(15):2324
references: 19633409
references: J Biol Chem. 1998 Mar 6;273(10):5858-68
references: 9488723
references: Int J Oncol. 2008 Aug;33(2):261-70
references: 18636146
references: J Biol Chem. 2012 Aug 31;287(36):30812-22
references: 22822074
references: Biochemistry. 1994 Jun 14;33(23):7033-40
references: 7516181
references: Nature. 2005 Apr 14;434(7035):907-13
references: 15829965
references: Philos Trans R Soc Lond B Biol Sci. 2009 Mar 12;364(1517):705-15
references: 19042181
references: Nucleic Acids Res. 2010 Jul;38(13):4274-84
references: 20308164
references: Methods Enzymol. 2000;322:15-8
references: 10914001