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PMID: 15060158 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

The human beta-globin replication initiation region consists of two modular independent replicators.

Molecular and cellular biology ·Vol. 24 ·No. 8 ·2004-04-00 ·Pages 3373-86

Wang L, Lin CM, Brooks S, Cimbora D, Groudine M, Aladjem MI

Abstract

Previous studies have shown that mammalian cells contain replicator sequences, which can determine where DNA replication initiates. However, the specific sequences that confer replicator activity were not identified. Here we report a detailed analysis of replicator sequences that dictate initiation of DNA replication from the human beta-globin locus. This analysis suggests that the beta-globin replication initiation region contains two adjacent, redundant replicators. Each replicator was capable of initiating DNA replication independently at ectopic sites. Within each of these two replicators, we identified short, discrete, nonredundant sequences, which cooperatively determine replicator activity. Experiments with somatic cell hybrids further demonstrated that the requirements for initiation at ectopic sites were similar to the requirements for initiation within native human chromosomes. The replicator clustering and redundancy exemplified in the human beta-globin locus may account for the extreme difficulty in identifying replicator sequences in mammalian cells and suggest that mammalian replication initiation sites may be determined by cooperative sequence modules.

MeSH Terms
Animals Base Sequence Cell Line DNA Replication Gene Transfer Techniques Globins/genetics,metabolism Humans Introns Molecular Sequence Data Mutagenesis, Site-Directed Regulatory Sequences, Nucleic Acid Replication Origin
Chemicals
Globins
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Wang Lixin
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
Lin Chii-Mei
Brooks Sarah
Cimbora Dan
Groudine Mark
Aladjem Mirit I
References (55)
55 references, click to expand
  1. The matrix attachment region in the Chinese hamster dihydrofolate reductase origin of replication may be required for local chromatid separation.
    Proc Natl Acad Sci U S A. 2003 Mar 18;100(6):3281-6 PMID: 12629222
  2. Multiple redundant sequence elements within the fission yeast ura4 replication origin enhancer.
    BMC Mol Biol. 2001;2:1 PMID: 11178109
  3. Transcriptional elements as components of eukaryotic origins of DNA replication.
    Cell. 1988 Mar 11;52(5):635-8 PMID: 3278812
  4. Site-specific ORC binding, pre-replication complex assembly and DNA synthesis at Schizosaccharomyces pombe replication origins.
    EMBO J. 2002 Oct 15;21(20):5567-76 PMID: 12374757
  5. Roles for internal and flanking sequences in regulating the activity of mating-type-silencer-associated replication origins in Saccharomyces cerevisiae.
    Genetics. 2001 Sep;159(1):35-45 PMID: 11560885
  6. Replication structure of the human beta-globin gene domain.
    Nature. 1993 Dec 9;366(6455):588-90 PMID: 8255298
  7. Human artificial chromosomes generated by modification of a yeast artificial chromosome containing both human alpha satellite and single-copy DNA sequences.
    Proc Natl Acad Sci U S A. 1999 Jan 19;96(2):592-7 PMID: 9892678
  8. Efficient modification of human chromosomal alleles using recombination-proficient chicken/human microcell hybrids.
    Nat Genet. 1996 Feb;12(2):174-82 PMID: 8563756
  9. Mapping replication units in animal cells.
    Cell. 1989 Jun 16;57(6):909-20 PMID: 2544294
  10. Participation of the human beta-globin locus control region in initiation of DNA replication.
    Science. 1995 Nov 3;270(5237):815-9 PMID: 7481774
  11. Distal sequences, but not ori-beta/OBR-1, are essential for initiation of DNA replication in the Chinese hamster DHFR origin.
    Mol Cell. 1998 Dec;2(6):797-806 PMID: 9885567
  12. Dynamics of association of origins of DNA replication with the nuclear matrix during the cell cycle.
    Nucleic Acids Res. 2001 Aug 1;29(15):3181-7 PMID: 11470875
  13. Activation of silent replication origins at autonomously replicating sequence elements near the HML locus in budding yeast.
    Mol Cell Biol. 1999 Sep;19(9):6098-109 PMID: 10454557
  14. A DNA unwinding element and an ARS consensus comprise a replication origin within a yeast chromosome.
    EMBO J. 1993 Dec;12(12):4521-31 PMID: 8223462
  15. Multiple determinants controlling activation of yeast replication origins late in S phase.
    Genes Dev. 1996 Jul 1;10(13):1595-607 PMID: 8682291
  16. Intergenic DNA and the sequence requirements for replication initiation in eukaryotes.
    Curr Opin Genet Dev. 1994 Apr;4(2):196-202 PMID: 8032196
  17. Making sense of eukaryotic DNA replication origins.
    Science. 2001 Oct 5;294(5540):96-100 PMID: 11588251
  18. Transcription interferes with elements important for chromosome maintenance in Saccharomyces cerevisiae.
    Mol Cell Biol. 1988 May;8(5):2184-94 PMID: 3290652
  19. The DNA unwinding element: a novel, cis-acting component that facilitates opening of the Escherichia coli replication origin.
    EMBO J. 1989 Dec 20;8(13):4335-44 PMID: 2556269
  20. Identification of an origin of bidirectional DNA replication in the ubiquitously expressed mammalian CAD gene.
    Mol Cell Biol. 1995 Aug;15(8):4136-48 PMID: 7623808
  21. Mapping replication fork direction by leading strand analysis.
    Methods. 1997 Nov;13(3):281-92 PMID: 9441854
  22. Yeast origins establish a strand bias for replicational mutagenesis.
    Mol Cell. 2002 Jul;10(1):207-13 PMID: 12150920
  23. Initiation sites are distributed at frequent intervals in the Chinese hamster dihydrofolate reductase origin of replication but are used with very different efficiencies.
    Mol Cell Biol. 2002 May;22(9):3053-65 PMID: 11940663
  24. The search for origins of DNA replication.
    Methods. 1997 Nov;13(3):211-9 PMID: 9441848
  25. A human DNA replication origin: localization and transcriptional characterization.
    Chromosoma. 1992;102(1 Suppl):S24-31 PMID: 1291239
  26. Multiple functional elements comprise a Mammalian chromosomal replicator.
    Mol Cell Biol. 2003 Mar;23(5):1832-42 PMID: 12589000
  27. Developmental changes in the Sciara II/9A initiation zone for DNA replication.
    Mol Cell Biol. 2002 Dec;22(24):8426-37 PMID: 12446763
  28. A mammalian origin of bidirectional DNA replication within the Chinese hamster RPS14 locus.
    Mol Cell Biol. 1994 Sep;14(9):5628-35 PMID: 8065299
  29. Genetic dissection of a mammalian replicator in the human beta-globin locus.
    Science. 1998 Aug 14;281(5379):1005-9 PMID: 9703500
  30. Cloning of the initiation region of a mammalian chromosomal replicon.
    Nature. 1983 Mar 31-Apr 6;302(5907):439-41 PMID: 6300683
  31. Identification of an origin of bidirectional DNA replication in mammalian chromosomes.
    Cell. 1990 Sep 7;62(5):955-65 PMID: 2393905
  32. Homeodomain protein binding sites, inverted repeats, and nuclear matrix attachment regions along the human beta-globin gene complex.
    J Cell Biochem. 1993 May;52(1):23-36 PMID: 8320272
  33. An origin of bidirectional DNA replication is located within a CpG island at the 3" end of the chicken lysozyme gene.
    Nucleic Acids Res. 1999 Aug 1;27(15):3009-17 PMID: 10454594
  34. Multiple sites of replication initiation in the human beta-globin gene locus.
    Nucleic Acids Res. 2001 Feb 1;29(3):809-17 PMID: 11160905
  35. Multiple orientation-dependent, synergistically interacting, similar domains in the ribosomal DNA replication origin of the fission yeast, Schizosaccharomyces pombe.
    Mol Cell Biol. 1998 Dec;18(12):7294-303 PMID: 9819416
  36. The dihydrofolate reductase origin of replication does not contain any nonredundant genetic elements required for origin activity.
    Mol Cell Biol. 2003 Feb;23(3):804-14 PMID: 12529386
  37. Polymorphism and divergence in the beta-globin replication origin initiation region.
    Mol Biol Evol. 2000 Jan;17(1):179-88 PMID: 10666717
  38. Inverted repeats, stem-loops, and cruciforms: significance for initiation of DNA replication.
    J Cell Biochem. 1996 Oct;63(1):1-22 PMID: 8891900
  39. Transition in specification of embryonic metazoan DNA replication origins.
    Science. 1995 Nov 10;270(5238):994-7 PMID: 7481806
  40. Replication initiation patterns in the beta-globin loci of totipotent and differentiated murine cells: evidence for multiple initiation regions.
    Mol Cell Biol. 2002 Jan;22(2):442-52 PMID: 11756541
  41. Two compound replication origins in Saccharomyces cerevisiae contain redundant origin recognition complex binding sites.
    Mol Cell Biol. 2001 Apr;21(8):2790-801 PMID: 11283258
  42. Multiple ORC-binding sites are required for efficient MCM loading and origin firing in fission yeast.
    EMBO J. 2003 Feb 17;22(4):964-74 PMID: 12574132
  43. Initiation of eukaryotic DNA replication: conservative or liberal?
    J Cell Physiol. 2000 Aug;184(2):139-50 PMID: 10867638
  44. Replication of the chicken beta-globin locus: early-firing origins at the 5' HS4 insulator and the rho- and betaA-globin genes show opposite epigenetic modifications.
    Mol Cell Biol. 2003 May;23(10):3536-49 PMID: 12724412
  45. The origin of a developmentally regulated Igh replicon is located near the border of regulatory domains for Igh replication and expression.
    Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13693-8 PMID: 12370427
  46. Sequence-independent DNA binding and replication initiation by the human origin recognition complex.
    Genes Dev. 2003 Aug 1;17(15):1894-908 PMID: 12897055
  47. Discrete start sites for DNA synthesis in the yeast ARS1 origin.
    Science. 1998 Jan 2;279(5347):95-8 PMID: 9417033
  48. Common structural features of replication origins in all life forms.
    J Cell Biochem. 1996 Mar 1;60(3):297-316 PMID: 8867806
  49. Transcription from efficient promoters can interfere with plasmid replication and diminish expression of plasmid specified genes.
    EMBO J. 1982;1(11):1399-404 PMID: 6327267
  50. Replication and subnuclear location dynamics of the immunoglobulin heavy-chain locus in B-lineage cells.
    Mol Cell Biol. 2002 Jul;22(13):4876-89 PMID: 12052893
  51. DNase I sensitive site in the core region of the human beta-globin origin of replication.
    J Cell Biochem. 2002;87(3):279-83 PMID: 12397609
  52. Identification of primary initiation sites for DNA replication in the hamster dihydrofolate reductase gene initiation zone.
    Mol Cell Biol. 1998 Jun;18(6):3266-77 PMID: 9584167
  53. The Chinese hamster dihydrofolate reductase replication origin beta is active at multiple ectopic chromosomal locations and requires specific DNA sequence elements for activity.
    Mol Cell Biol. 2001 Feb;21(4):1098-110 PMID: 11158297
  54. Regulation of chromosome replication.
    Annu Rev Biochem. 2000;69:829-80 PMID: 10966477
  55. Characterization of an episome produced in hamster cells that amplify a transfected CAD gene at high frequency: functional evidence for a mammalian replication origin.
    Mol Cell Biol. 1987 May;7(5):1740-50 PMID: 2885742
Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.24.8.3373-3386.2004
Published
2004-04-00
Pages
3373-86
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC381644
Subset
IM
Grants
NIDDK NIH HHS · R37 DK044746 · United States
NIDDK NIH HHS · DK44746 · United States
NHLBI NIH HHS · HL57620 · United States
External Links
PubMed source DOI: 10.1128/MCB.24.8.3373-3386.2004 PMC Full Text View journal details
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