title: Back to the origin: reconsidering replication, transcription, epigenetics, and cell cycle control.
abstract: In bacteria, replication is a carefully orchestrated event that unfolds the same way for each bacterium and each cell division. The process of DNA replication in bacteria optimizes cell growth and coordinates high levels of simultaneous replication and transcription. In metazoans, the organization of replication is more enigmatic. The lack of a specific sequence that defines origins of replication has, until recently, severely limited our ability to define the organizing principles of DNA replication. This question is of particular importance as emerging data suggest that replication stress is an important contributor to inherited genetic damage and the genomic instability in tumors. We consider here the replication program in several different organisms including recent genome-wide analyses of replication origins in humans. We review recent studies on the role of cytosine methylation in replication origins, the role of transcriptional looping and gene gating in DNA replication, and the role of chromatin's 3-dimensional structure in DNA replication. We use these new findings to consider several questions surrounding DNA replication in metazoans: How are origins selected? What is the relationship between replication and transcription? How do checkpoints inhibit origin firing? Why are there early and late firing origins? We then discuss whether oncogenes promote cancer through a role in DNA replication and whether errors in DNA replication are important contributors to the genomic alterations and gene fusion events observed in cancer. We conclude with some important areas for future experimentation.
authors: Princeton University, Princeton, NJ, USA.
authors: Adam G
authors: AG
authors: Evertts
authors: Hilary A
authors: HA
authors: Coller
keywords: checkpoints; epigenetics; origin; replication; replicon; transcription
references: Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):2656-61
references: 10077566
references: Mol Gen Genet. 1985;201(3):467-76
references: 3911026
references: Nat Med. 1996 Jun;2(6):682-5
references: 8640560
references: EMBO J. 1998 Apr 15;17(8):2426-35
references: 9545253
references: EMBO J. 2006 Nov 1;25(21):5171-9
references: 17053780
references: EMBO Rep. 2006 Aug;7(8):806-11
references: 16799461
references: Cell. 1988 Nov 18;55(4):637-43
references: 3052854
references: Mutat Res. 1999 Jul;437(1):11-20
references: 10425387
references: Genome Res. 2003 Jan;13(1):37-45
references: 12529304
references: Mol Cell. 2012 Mar 30;45(6):710-8
references: 22464441
references: Science. 2009 Oct 9;326(5950):289-93
references: 19815776
references: Bioessays. 1999 Jan;21(1):5-16
references: 10070250
references: Nature. 1991 Oct 17;353(6345):628-32
references: 1656277
references: Annu Rev Biochem. 1993;62:29-63
references: 8352592
references: EMBO J. 2011 Nov 11;30(23):4805-14
references: 22081107
references: Cell Cycle. 2005 Jan;4(1):172-6
references: 15611667
references: Mol Cell Biol. 1988 Nov;8(11):4927-35
references: 3062373
references: Nucleic Acids Res. 1991 Dec;19(25):7061-5
references: 1662803
references: J Mol Biol. 1985 Dec 20;186(4):773-90
references: 3912515
references: Mol Cell. 2003 May;11(5):1323-36
references: 12769855
references: Nature. 2006 Nov 30;444(7119):638-42
references: 17136094
references: Science. 1996 Apr 5;272(5258):107-9
references: 8600517
references: Cell. 2009 Sep 4;138(5):870-84
references: 19737516
references: Science. 1995 Feb 24;267(5201):1131-7
references: 7855590
references: Biochim Biophys Acta. 2010 Aug;1799(8):533-8
references: 20601280
references: Nature. 1993 Nov 4;366(6450):33-9
references: 8232535
references: Nat Cell Biol. 2001 Mar;3(3):289-95
references: 11231579
references: EMBO J. 2004 Feb 25;23(4):897-907
references: 14765124
references: Nature. 2007 Jun 14;447(7146):799-816
references: 17571346
references: Nat Genet. 2009 Jul;41(7):849-53
references: 19543269
references: Curr Opin Genet Dev. 2009 Apr;19(2):142-9
references: 19345088
references: Mol Cell Biol. 2008 Sep;28(17):5265-74
references: 18573882
references: PLoS Comput Biol. 2011 Dec;7(12):e1002322
references: 22219720
references: Bioessays. 2005 Nov;27(11):1107-16
references: 16237674
references: Mol Cell Biol. 1999 Jan;19(1):547-55
references: 9858578
references: Genes Dev. 2004 Dec 15;18(24):3094-105
references: 15601823
references: J Cell Biochem. 2000 Jun 6;78(3):442-57
references: 10861842
references: Science. 1997 Sep 5;277(5331):1453-62
references: 9278503
references: Trends Microbiol. 2002 Sep;10(9):393-5
references: 12217498
references: Cell. 2012 Jan 20;148(1-2):99-111
references: 22265405
references: Cell. 2009 Sep 4;138(5):855-69
references: 19737515
references: Mol Cell. 2003 Dec;12(6):1525-36
references: 14690605
references: J Cell Biol. 2001 Jan 8;152(1):15-25
references: 11149917
references: J Cell Biochem. 2008 Oct 1;105(2):321-9
references: 18680119
references: PLoS One. 2012;7(9):e44196
references: 23028501
references: Nat Biotechnol. 2011 Nov 20;29(12):1103-8
references: 22101487
references: Science. 1992 Feb 14;255(5046):817-23
references: 1536007
references: Nat Struct Mol Biol. 2008 Jul;15(7):722-9
references: 18536724
references: Genes Dev. 2005 Dec 15;19(24):2969-78
references: 16319194
references: Proc Natl Acad Sci U S A. 1996 Feb 20;93(4):1498-503
references: 8643660
references: Nat Rev Mol Cell Biol. 2002 Jun;3(6):430-40
references: 12042765
references: Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3418-22
references: 8159762
references: J Biol Chem. 2004 Jul 2;279(27):28071-81
references: 15123715
references: Proc Natl Acad Sci U S A. 2011 Oct 18;108(42):17360-5
references: 21987784
references: Proc Natl Acad Sci U S A. 2004 May 4;101(18):6923-8
references: 15105447
references: Science. 1989 Nov 10;246(4931):808-10
references: 2683084
references: EMBO Rep. 2004 Jul;5(7):686-91
references: 15229645
references: Cancer Cell. 2010 Mar 16;17(3):225-34
references: 20171147
references: Proc Natl Acad Sci U S A. 1980 Nov;77(11):6329-33
references: 7005897
references: Mol Gen Genet. 1984;193(3):473-8
references: 6369074
references: PLoS Genet. 2010 Jan 15;6(1):e1000810
references: 20090829
references: Cell. 2005 Oct 7;123(1):13-24
references: 16213209
references: Cell Cycle. 2007 Jul 15;6(14):1705-12
references: 17622799
references: PLoS Biol. 2008 Oct 7;6(10):e245
references: 18842067
references: Science. 2003 Jun 6;300(5625):1542-8
references: 12791985
references: Nat Cell Biol. 2004 Jul;6(7):648-55
references: 15220931
references: Front Biosci. 1999 Dec 01;4:D859-68
references: 10577395
references: Br Med Bull. 1973 Sep;29(3):192-5
references: 4807321
references: Cell. 2011 Sep 30;147(1):107-19
references: 21962511
references: Genome Biol. 2012 Apr 24;13(4):R27
references: 22531001
references: Proc Natl Acad Sci U S A. 2008 Oct 14;105(41):15837-42
references: 18838675
references: Science. 1995 Nov 3;270(5237):815-9
references: 7481774
references: Genome Res. 2011 Sep;21(9):1438-49
references: 21750104
references: Genes Dev. 2009 Nov 15;23(22):2610-24
references: 19933151
references: EMBO J. 1999 Oct 15;18(20):5703-13
references: 10523313
references: Science. 2006 Oct 13;314(5797):268-74
references: 16959974
references: Nucleic Acids Res. 2012 Oct;40(18):9021-35
references: 22772991
references: Nat Rev Genet. 2008 Mar;9(3):204-17
references: 18227811
references: Genes Dev. 2009 Mar 1;23(5):589-601
references: 19270159
references: J Biol Chem. 1992 Nov 15;267(32):23083-6
references: 1429655
references: Proc Natl Acad Sci U S A. 2004 Sep 28;101(39):14085-90
references: 15371597
references: DNA Repair (Amst). 2006 Sep 8;5(9-10):1126-35
references: 16807141
references: Science. 2001 Oct 5;294(5540):115-21
references: 11588253
references: PLoS Genet. 2009 Jan;5(1):e1000327
references: 19180184
references: C R Hebd Seances Acad Sci. 1963 Jan 2;256:298-300
references: 13964280
references: Nature. 2005 Apr 14;434(7035):864-70
references: 15829956
references: Cell. 2012 Mar 2;148(5):908-21
references: 22341456
references: Nucleic Acids Res. 1994 Nov 25;22(23):5038-46
references: 7800497
references: Oncogene. 2008 May 22;27(23):3345-59
references: 18084325
references: Nat Biotechnol. 2011 Nov 20;29(12):1109-13
references: 22101486
references: J Mol Evol. 1998 Dec;47(6):691-6
references: 9847411
references: Nature. 2008 Mar 6;452(7183):112-5
references: 18322535
references: Nature. 1993 Dec 9;366(6455):588-90
references: 8255298
references: PLoS Genet. 2006 Apr;2(4):e48
references: 16604155
references: Mol Cell Biol. 2006 Jul;26(14):5270-83
references: 16809765
references: Curr Opin Genet Dev. 2006 Apr;16(2):177-83
references: 16503127
references: Am J Hum Genet. 2009 Mar;84(3):339-50
references: 19232554
references: J Biol Chem. 2000 Dec 15;275(50):39773-8
references: 11005825
references: Mol Cell. 2006 Mar 3;21(5):719-26
references: 16507369
references: Nat Rev Mol Cell Biol. 2010 Mar;11(3):208-19
references: 20177396
references: J Cell Biochem. 2009 Oct 1;108(2):400-7
references: 19585526
references: Experientia. 1970 Sep 26;26(9):1020-1
references: 5478612
references: J Theor Biol. 2000 Feb 21;202(4):305-14
references: 10666362
references: Nature. 2001 Jun 28;411(6841):1068-73
references: 11429609
references: Annu Rev Biochem. 2001;70:369-413
references: 11395412
references: EMBO J. 1996 Oct 15;15(20):5636-46
references: 8896457
references: Curr Top Dev Biol. 2006;76:129-84
references: 17118266
references: Science. 1995 Nov 10;270(5238):994-7
references: 7481806
references: J Cell Biochem. 2003 Apr 1;88(5):923-31
references: 12616531
references: Mol Biol Evol. 2009 Apr;26(4):729-41
references: 19126867
references: Genes Dev. 1996 Nov 15;10(22):2819-30
references: 8918884
references: Science. 2002 Jul 26;297(5581):599-602
references: 12142537
references: Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10786-91
references: 9380711
references: Nature. 1999 Sep 16;401(6750):297-300
references: 10499591
references: Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):10020-5
references: 9707593
references: Genome Res. 2007 Sep;17(9):1278-85
references: 17675363
references: Semin Cell Dev Biol. 2011 Oct;22(8):866-74
references: 22020070
references: Microbiology (Reading). 2004 Jun;150(Pt 6):1609-1627
references: 15184548
references: Cold Spring Harb Symp Quant Biol. 1974;38:205-23
references: 4208784
references: Genome Res. 2011 Mar;21(3):377-89
references: 21173031
references: Cell. 2006 Jun 30;125(7):1283-96
references: 16814715
references: Proc Natl Acad Sci U S A. 2005 Jan 11;102(2):337-42
references: 15623550
references: Trends Genet. 2002 Jun;18(6):291-4
references: 12044357
references: Nature. 2008 Dec 11;456(7223):762-6
references: 19020502
references: Nucleic Acids Res. 2012 Mar;40(5):2010-9
references: 22086957
references: Cancer Cell. 2010 Dec 14;18(6):553-67
references: 21130701
references: Proc Natl Acad Sci U S A. 2005 Jul 12;102(28):9836-41
references: 15985556
references: J Mol Biol. 2008 Jan 4;375(1):12-9
references: 17999930
references: Cell. 1984 Aug;38(1):55-64
references: 6380762
references: Annu Rev Genet. 2007;41:237-80
references: 17630848
references: Cell. 2011 Jan 7;144(1):27-40
references: 21215367
references: Mol Microbiol. 2006 Mar;59(5):1506-18
references: 16468991
references: Cell. 2008 Oct 17;135(2):308-21
references: 18957205
references: J Biol Chem. 2012 Apr 27;287(18):14615-20
references: 22442146
references: Mol Biol Cell. 2010 Feb 1;21(3):393-404
references: 19955211
references: Mol Cell. 2009 Jun 26;34(6):722-34
references: 19560424
references: Nucleic Acids Res. 1998 May 15;26(10):2286-90
references: 9580676
references: Oncogene. 1993 Nov;8(11):2889-96
references: 8414493
references: Mol Cell Biol. 2005 Feb;25(3):888-95
references: 15657418
references: Annu Rev Genet. 1977;11:297-347
references: 339818
references: Genes Dev. 2003 May 1;17(9):1071-7
references: 12730130
references: EMBO Rep. 2003 Nov;4(11):1048-53
references: 14566325
references: PLoS Genet. 2009 Apr;5(4):e1000446
references: 19360092
references: Cell. 1988 Jun 3;53(5):679-86
references: 3286014
references: Proc Natl Acad Sci U S A. 2007 Mar 27;104(13):5608-13
references: 17372224
references: J Natl Cancer Inst. 2010 Jul 7;102(13):932-41
references: 20513808
references: Genome Res. 2010 Jun;20(6):761-70
references: 20430782
references: Genes Dev. 2010 Apr 15;24(8):748-53
references: 20351051
references: PLoS Genet. 2011 Dec;7(12):e1002386
references: 22144908
references: Cell Cycle. 2004 Feb;3(2):223-9
references: 14712093
references: Science. 2010 Jan 29;327(5965):590-2
references: 20110508
references: Nature. 2008 Mar 6;452(7183):45-50
references: 18322525
references: Mol Biol Evol. 1996 May;13(5):660-5
references: 8676740
references: Science. 1993 Dec 10;262(5140):1728-31
references: 8259517
references: Genome Biol. 2004;5(4):R22
references: 15059255
references: Nat Struct Mol Biol. 2006 Aug;13(8):676-83
references: 16829961
references: Cell. 1980 Oct;21(3):761-71
references: 6254667
references: Bioessays. 2003 Feb;25(2):116-25
references: 12539237
references: EMBO J. 1997 Sep 15;16(18):5775-83
references: 9312035
references: EMBO J. 1995 Jun 1;14(11):2570-9
references: 7781610
references: Genes Cells. 1997 Nov;2(11):667-78
references: 9491801
references: PLoS Genet. 2010 Sep 02;6(9):e1001092
references: 20824081
references: Nature. 1997 Nov 20;390(6657):249-56
references: 9384377
references: J Cell Biochem. 2009 Mar 1;106(4):512-20
references: 19173303
references: Proc Natl Acad Sci U S A. 1994 May 24;91(11):5124-8
references: 8197195
references: Nature. 2002 Dec 19-26;420(6917):833-7
references: 12490953
references: Science. 1992 Nov 20;258(5086):1362-5
references: 1455232
references: Nat Rev Mol Cell Biol. 2008 Oct;9(10):810-5
references: 18698328
references: Cell Cycle. 2004 Jul;3(7):941-5
references: 15190204
references: Mol Cell. 2002 May;9(5):1067-78
references: 12049742
references: Nat Genet. 2006 Sep;38(9):1038-42
references: 16906162
references: Mol Cell Biol. 1993 Oct;13(10):6600-13
references: 8413256
references: Nucleic Acids Res. 2003 Nov 15;31(22):6570-7
references: 14602916
references: Genes Dev. 2011 Jun 15;25(12):1320-7
references: 21685366
references: Genome Biol. 2007;8(8):R169
references: 17705870
references: Genome Res. 2012 Jan;22(1):25-34
references: 22090376
references: Mol Cell. 2002 Nov;10(5):1223-33
references: 12453428
references: Curr Opin Genet Dev. 2009 Jun;19(3):196-204
references: 19477115
references: Nat Cell Biol. 2002 Dec;4(12):998-1002
references: 12447382
references: Cell. 2011 Jul 22;146(2):233-46
references: 21784245
references: Proc Natl Acad Sci U S A. 1966 Mar;55(3):599-606
references: 5221245
references: J Mol Biol. 2000 Jul 28;300(5):1133-42
references: 10903859
references: Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2865-9
references: 8385347
references: Chromosome Res. 2010 Jan;18(1):147-61
references: 20205354
references: J Clin Oncol. 2012 Apr 20;30(12):1350-7
references: 22430270
references: Science. 2008 Mar 7;319(5868):1352-5
references: 18323444
references: Science. 2002 Jul 26;297(5581):552-7
references: 12142524
references: Genome Res. 2011 Nov;21(11):1851-62
references: 21914852
references: Cell. 2007 Dec 28;131(7):1235-47
references: 18160035
references: PLoS One. 2009 Jun 18;4(6):e5951
references: 19554081
references: Genes Dev. 1999 Sep 15;13(18):2360-4
references: 10500092
references: Proc Natl Acad Sci U S A. 1980 Aug;77(8):4559-63
references: 6449009
references: Cancer Sci. 2012 Feb;103(2):269-73
references: 22034964
references: J Biol Chem. 2003 Feb 7;278(6):4295-304
references: 12424256
references: Cell Div. 2008 Jan 22;3:3
references: 18211690
references: PLoS Comput Biol. 2005 Jun;1(1):e12
references: 16103901
references: Mol Biol Cell. 2006 Jan;17(1):308-16
references: 16251353
references: Mol Biol Evol. 2011 Aug;28(8):2327-37
references: 21368316
references: Chromosome Res. 1996 Aug;4(5):365-71
references: 8871825
references: Cell. 2011 Sep 16;146(6):889-903
references: 21925314
references: Oncogene. 2007 Oct 18;26(48):6948-53
references: 17486057
references: Exp Cell Res. 1998 Jan 10;238(1):220-30
references: 9457075
references: Am J Hum Genet. 1987 Feb;40(2):151-73
references: 3551593
references: Mol Cell. 2008 Apr 25;30(2):156-66
references: 18439895
references: EMBO J. 2003 Sep 15;22(18):4719-27
references: 12970184
references: Genes Dev. 2006 Jul 15;20(14):1874-9
references: 16847347
references: Cell Cycle. 2012 Nov 15;11(22):4281-3
references: 22983127
references: J Mol Biol. 2000 Feb 25;296(3):769-86
references: 10677280
references: Science. 1996 May 3;272(5262):745-6
references: 8614839
references: EMBO J. 2012 Sep 12;31(18):3678-90
references: 22850673
references: Nat Cell Biol. 2006 Dec;8(12):1313-6
references: 17139278
references: Leuk Lymphoma. 2012 Dec;53(12):2423-9
references: 22616558
references: Genes Dev. 1990 Oct;4(10):1637-49
references: 2249769
references: PLoS Comput Biol. 2012;8(4):e1002443
references: 22496629
references: EMBO J. 2000 Nov 1;19(21):5824-34
references: 11060033
references: Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3720-5
references: 9520433
references: Oncogene. 2005 Apr 18;24(17):2827-43
references: 15838518
references: Nature. 2006 Nov 30;444(7119):633-7
references: 17136093
references: Nat Rev Mol Cell Biol. 2003 Jan;4(1):25-32
references: 12511866
references: Curr Opin Cell Biol. 2009 Dec;21(6):778-84
references: 19913398
references: Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3940-4
references: 10097142
references: Semin Cancer Biol. 2010 Aug;20(4):222-33
references: 20541013
references: Cell. 2006 Jun 30;125(7):1233-5
references: 16814710
references: Cell. 1981 May;24(2):283-4
references: 6263494
references: Annu Rev Biochem. 2002;71:333-74
references: 12045100
references: Trends Genet. 1997 Jun;13(6):240-5
references: 9196330
references: Mol Biol Cell. 2006 Dec;17(12):5337-45
references: 17005913
references: Curr Opin Cell Biol. 2005 Jun;17(3):251-6
references: 15901493
references: Mol Cell Biol. 1997 Feb;17(2):553-63
references: 9001208
references: Mol Cell Biol. 1990 Apr;10(4):1439-51
references: 2181275
references: DNA Repair (Amst). 2004 Aug-Sep;3(8-9):901-8
references: 15279775
references: Nat Immunol. 2003 Mar;4(3):235-40
references: 12548284
references: Genes Dev. 2001 Aug 15;15(16):2060-8
references: 11511538
references: Nat Genet. 2003 Aug;34(4):377-8
references: 12847524
references: Int J Oncol. 2012 Oct;41(4):1325-36
references: 22825915
references: Hum Mol Genet. 2004 Jan 15;13(2):191-202
references: 14645202
references: Mol Cell. 1999 Dec;4(6):983-93
references: 10635323
references: EMBO J. 1995 Dec 15;14(24):6218-28
references: 8557041
references: Hum Mol Genet. 2009 Jun 15;18(12):2188-203
references: 19324899
references: J Cell Biol. 1998 Mar 23;140(6):1285-95
references: 9508763
references: Genes Dev. 2009 May 1;23(9):1077-90
references: 19417103
references: Genes Dev. 2007 Mar 1;21(5):497-518
references: 17344412
references: Mol Biol Evol. 2002 Aug;19(8):1350-8
references: 12140247
references: Mol Cell Biol. 1994 Apr;14(4):2651-63
references: 8139565
references: Genes Dev. 2007 Aug 1;21(15):1921-36
references: 17671091
references: Science. 2000 Mar 17;287(5460):2023-6
references: 10720330
references: Science. 2001 Oct 5;294(5540):96-100
references: 11588251
references: Nature. 2001 Aug 2;412(6846):557-61
references: 11484058
references: Chromosoma. 2008 Aug;117(4):319-31
references: 18427828
references: Cell Cycle. 2005 Feb;4(2):235-8
references: 15655372
references: Genes Dev. 1999 Mar 15;13(6):637-42
references: 10090719
references: Genome Res. 2012 Oct;22(10):1833-44
references: 22628462
references: J Virol. 1991 Jul;65(7):3496-503
references: 1645781
references: Cold Spring Harb Symp Quant Biol. 2010;75:143-53
references: 21139067
references: Genome Res. 2007 Jun;17(6):865-76
references: 17568004
references: Nature. 2012 Feb 15;483(7390):474-8
references: 22343901
references: Genes Dev. 1999 Jan 15;13(2):146-51
references: 9925638
references: Gene. 1999 Sep 30;238(1):65-77
references: 10570985
references: J Cell Sci. 2004 Oct 15;117(Pt 22):5353-65
references: 15466893
references: PLoS Genet. 2010 Jul 01;6(7):e1001011
references: 20617169
references: Mol Cell Biol. 1992 Aug;12(8):3499-506
references: 1630457
references: Cell Cycle. 2010 Jul 1;9(13):2537-43
references: 20581460
references: Nature. 2007 Jul 26;448(7152):445-51
references: 17597761
references: Mol Cell Biol. 2004 Jun;24(11):4769-80
references: 15143171
references: Mol Cell. 2001 Jan;7(1):21-30
references: 11172708
references: Nature. 2006 Jun 8;441(7094):770-3
references: 16760982
references: Nat Rev Mol Cell Biol. 2010 Oct;11(10):728-38
references: 20861881
references: Curr Biol. 2000 Apr 20;10(8):479-82
references: 10801416
references: J Cell Biol. 1998 Dec 14;143(6):1415-25
references: 9852140
references: Nat Cell Biol. 2004 Aug;6(8):721-30
references: 15247921
references: Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):13919-24
references: 8943036
references: Nature. 2005 Apr 14;434(7035):907-13
references: 15829965
references: Curr Opin Genet Dev. 2012 Jun;22(3):211-20
references: 22440479
references: J Bacteriol. 1982 Feb;149(2):458-68
references: 6173374
references: Curr Opin Cell Biol. 2002 Jun;14(3):377-83
references: 12067662