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Human Molecular Genetics Advance Access published online on July 28, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl187
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Published by Oxford University Press 2006
Received June 3, 2006
Revised July 20, 2006
Accepted July 20, 2006

Article

Cooperative Sequence Modules Determine Replication Initiation Sites at the Human {beta}-Globin Locus

Lixin Wang 1, Chii Mei Lin 1, Joseph O. Lopreiato 1, and Mirit I Aladjem 2 *

1 Laboratory of Molecular Pharmacology, National Cancer Institute, Bethesda, Maryland
2 Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, 37 Convent Dr., Bethesda, Maryland

* To whom correspondence should be addressed.
Mirit I Aladjem, E-mail: aladjemm{at}mail.nih.gov


  Abstract

The human beta globin locus contains two adjacent replicators, each capable of initiating DNA replication when transferred from its native locus to ectopic sites. Here we report a detailed analysis of the sequence requirements for replication initiation from these replicators. In both replicators, initiation required a combination of an asymmetric purine:pyrimidine sequence and several AT-rich stretches. Modules from the two replicators could combine to initiate replication. AT-rich sequences were essential for replicator activity: a low frequency of initiation was observed in DNA fragments that included a short stretch of AT-rich sequences whereas inclusion of additional AT-rich stretches increased initiation efficiency. By contrast, replication initiated at a low level without the asymmetric purine:pyrimidine modules but they were required in synergy to achieve efficient initiation. These data support a combinatorial model for replicator activity and suggest that the initiation of DNA replication requires interaction between at least two distinct sequence modules.


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