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Molecular and Cellular Biology, April 2004, p. 3373-3386, Vol. 24, No. 8
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.8.3373-3386.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

The Human ß-Globin Replication Initiation Region Consists of Two Modular Independent Replicators

Lixin Wang,1 Chii-Mei Lin,1 Sarah Brooks,1 Dan Cimbora,2 Mark Groudine,2 and Mirit I. Aladjem1*

Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland,1 Fred Hutchinson Cancer Research Center, Seattle, Washington2

Received 21 August 2003/ Returned for modification 15 October 2003/ Accepted 15 January 2004

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 ß-globin locus. This analysis suggests that the ß-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 ß-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.

* Corresponding author. Mailing address: Laboratory of Molecular Pharmacology, DBS/NCI/NIH, Bldg. 37, Rm. 5056, 37 Convent Dr., Bethesda, MD 20892-4255. Phone: (301) 435-2848. Fax: (301) 402-0752. E-mail: aladjemm{at}mail.nih.gov.

Molecular and Cellular Biology, April 2004, p. 3373-3386, Vol. 24, No. 8
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.8.3373-3386.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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