title: Next-generation sequencing of apoptotic DNA breakpoints reveals association with actively transcribed genes and gene translocations.
abstract: DNA fragmentation is a well-recognized hallmark of apoptosis. However, the precise DNA sequences cleaved during apoptosis triggered by distinct mechanisms remain unclear. We used next-generation sequencing of DNA fragments generated in Actinomycin D-treated human HL-60 leukemic cells to generate a high-throughput, global map of apoptotic DNA breakpoints. These data highlighted that DNA breaks are non-random and show a significant association with active genes and open chromatin regions. We noted that transcription factor binding sites were also enriched within a fraction of the apoptotic breakpoints. Interestingly, extensive apoptotic cleavage was noted within genes that are frequently translocated in human cancers. We speculate that the non-random fragmentation of DNA during apoptosis may contribute to gene translocations and the development of human cancers.
authors.affiliation: A*STAR-Duke-NUS Neuroscience Partnership, Duke-NUS Graduate Medical School Singapore, Singapore, Singapore.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Fullwood
authors.forename: Joanne
authors.initials: J
authors.lastname: Lee
authors.forename: Lifang
authors.initials: L
authors.lastname: Lin
authors.forename: Guoliang
authors.initials: G
authors.lastname: Li
authors.forename: Mikael
authors.initials: M
authors.lastname: Huss
authors.forename: Patrick
authors.initials: P
authors.lastname: Ng
authors.forename: Wing-Kin
authors.initials: WK
authors.lastname: Sung
authors.forename: Shirish
authors.initials: S
authors.lastname: Shenolikar
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D053938:DNA Fragmentation; D003609:Dactinomycin / Q000494:pharmacology; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D014157:Transcription Factors; D014158:Transcription, Genetic; D014178:Translocation, Genetic
chemical_list: D014157:Transcription Factors; D003609:Dactinomycin
references.citation: Mol Neurobiol. 2010 Aug;42(1):4-9
references.pmid: 20552413
references.citation: Int J Gynecol Cancer. 2006 May-Jun;16(3):1432-8
references.pmid: 16803542
references.citation: Genome Biol. 2008;9(9):R137
references.pmid: 18798982
references.citation: Nature. 1998 Jan 1;391(6662):43-50
references.pmid: 9422506
references.citation: Nature. 2001 Feb 15;409(6822):860-921
references.pmid: 11237011
references.citation: Nature. 2005 Jan 20;433(7023):278-85
references.pmid: 15662416
references.citation: Cancer Res. 2007 Nov 15;67(22):10782-8
references.pmid: 18006822
references.citation: BMJ. 2001 Jun 23;322(7301):1536-8
references.pmid: 11420279
references.citation: Br J Cancer. 2003 Jan 27;88(2):210-6
references.pmid: 12610505
references.citation: Oncogene. 2001 Jun 7;20(26):3449-55
references.pmid: 11423996
references.citation: J Biol Chem. 2005 Jan 7;280(1):826-31
references.pmid: 15485892
references.citation: Mol Cell Biol. 1997 Jul;17(7):4070-9
references.pmid: 9199342
references.citation: Trends Cell Biol. 1995 Jan;5(1):21-6
references.pmid: 14731429
references.citation: Nat Rev Cancer. 2004 Mar;4(3):177-83
references.pmid: 14993899
references.citation: Methods Mol Biol. 2000;132:365-86
references.pmid: 10547847
references.citation: Br J Cancer. 2006 Dec 18;95(12):1696-700
references.pmid: 17146478
references.citation: Hepatology. 2010 Feb;51(2):642-53
references.pmid: 20054869
references.citation: Cell. 2011 Mar 4;144(5):646-74
references.pmid: 21376230
references.citation: Nature. 2010 Oct 28;467(7319):1061-73
references.pmid: 20981092
references.citation: Bioinformatics. 2006 May 1;22(9):1036-46
references.pmid: 16500937
references.citation: J Biol Chem. 2001 Aug 24;276(34):31590-5
references.pmid: 11406628
references.citation: Int J Biochem Cell Biol. 2000 Nov-Dec;32(11-12):1103-21
references.pmid: 11137451
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4537-42
references.pmid: 15070753
references.citation: Cell Mol Life Sci. 2009 Jan;66(2):263-74
references.pmid: 18810317
references.citation: Leukemia. 1997 Apr;11(4):490-6
references.pmid: 9096688
references.citation: Cell Death Differ. 2003 Mar;10(3):278-89
references.pmid: 12700628
references.citation: Cancer Treat Rev. 2008 Dec;34(8):737-49
references.pmid: 18722718
references.citation: Biochem J. 2009 Aug 27;422(3):543-51
references.pmid: 19558368
references.citation: Cell Death Differ. 2010 Aug;17(8):1238-43
references.pmid: 20467440
references.citation: Oncogene. 2006 Aug 31;25(39):5370-6
references.pmid: 16619042
references.citation: Proc Natl Acad Sci U S A. 2001 May 22;98(11):6407-11
references.pmid: 11353826
references.citation: Am J Hum Genet. 2006 Nov;79(5):779-91
references.pmid: 17033956
references.citation: Genome Res. 2011 Mar;21(3):456-64
references.pmid: 21106903
references.citation: Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4230-5
references.pmid: 20160104
references.citation: Annu Rev Genet. 1998;32:7-31
references.pmid: 9928473
references.citation: Nucleic Acids Res. 2010 Jan;38(Database issue):D620-5
references.pmid: 19920125
references.citation: Nucleic Acids Res. 2010 Jan;38(Database issue):D613-9
references.pmid: 19906737
references.citation: Cell Cycle. 2010 Aug 1;9(15):2986-95
references.pmid: 20647765
references.citation: Cancer Res. 1999 Aug 1;59(15):3712-8
references.pmid: 10446986
references.citation: Cell. 2011 Jan 7;144(1):27-40
references.pmid: 21215367
references.citation: PLoS One. 2009;4(4):e5010
references.pmid: 19347039
references.citation: Cardiovasc Res. 2000 Feb;45(3):528-37
references.pmid: 10728374
references.citation: Annu Rev Genet. 2007;41:169-92
references.pmid: 17608616
references.citation: Nature. 1999 Feb 4;397(6718):441-6
references.pmid: 9989411
references.citation: Cell. 2007 May 18;129(4):823-37
references.pmid: 17512414
references.citation: Science. 2001 Nov 16;294(5546):1477-8
references.pmid: 11711663
references.citation: J Biol Chem. 2000 Mar 17;275(11):8226-32
references.pmid: 10713148
references.citation: Cell. 2008 Mar 7;132(5):887-98
references.pmid: 18329373
references.citation: Blood. 2008 Sep 15;112(6):2183-9
references.pmid: 18779403
references.citation: Carcinogenesis. 2000 Mar;21(3):485-95
references.pmid: 10688869
references.citation: Nature. 2008 Feb 14;451(7180):796-801
references.pmid: 18235444
references.citation: Nucleic Acids Res. 1998 Oct 1;26(19):4422-5
references.pmid: 9742244
references.citation: Br J Cancer. 1972 Aug;26(4):239-57
references.pmid: 4561027
references.citation: Proc Natl Acad Sci U S A. 2009 Sep 1;106(35):14926-31
references.pmid: 19706456
references.citation: J Cell Biol. 1996 Dec;135(5):1369-76
references.pmid: 8947557
references.citation: Hum Mol Genet. 2001 Oct 15;10(22):2481-91
references.pmid: 11709535
references.citation: Blood. 1999 Jun 1;93(11):3956-63
references.pmid: 10339505
references.citation: FASEB J. 2006 Aug;20(10):1611-21
references.pmid: 16873884
references.citation: Cell. 1995 Jan 27;80(2):293-9
references.pmid: 7834749
references.citation: Biochem Biophys Res Commun. 2010 May 21;396(1):147-51
references.pmid: 20494129
references.citation: J Biol Chem. 2005 Mar 11;280(10):9586-94
references.pmid: 15613478
references.citation: Mol Cell Biol. 2008 Dec;28(23):6989-7000
references.pmid: 18794359
references.citation: Mol Cell Proteomics. 2005 Jan;4(1):44-55
references.pmid: 15567892
references.citation: Proc Natl Acad Sci U S A. 2004 Nov 30;101(48):16837-42
references.pmid: 15550541
references.citation: Cancer Genet Cytogenet. 2002 Oct 15;138(2):95-101
references.pmid: 12505251
references.citation: Nucleic Acids Res. 2011 Jul;39(Web Server issue):W391-9
references.pmid: 21602269
references.citation: PLoS Biol. 2006 Jun;4(6):e180
references.pmid: 16700628
references.citation: Chromosoma. 2010 Aug;119(4):351-60
references.pmid: 20174815
references.citation: Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1504-9
references.pmid: 16432220