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Molecular and Cellular Biology, February 2006, p. 1098-1108, Vol. 26, No. 3
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.3.1098-1108.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Regulation of Replication Licensing by Acetyltransferase Hbo1

Masayoshi Iizuka,1,{dagger} Tomoko Matsui,2,{dagger} Haruhiko Takisawa,2* and M. Mitchell Smith1*

Department of Microbiology, University of Virginia Health System, Charlottesville, Virginia 22908,1 Department of Biology, Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043, Japan2

Received 26 July 2005/ Returned for modification 20 August 2005/ Accepted 14 November 2005

The initiation of DNA replication is tightly regulated in eukaryotic cells to ensure that the genome is precisely duplicated once and only once per cell cycle. This is accomplished by controlling the assembly of a prereplicative complex (pre-RC) which involves the sequential binding to replication origins of the origin recognition complex (ORC), Cdc6/Cdc18, Cdt1, and the minichromosome maintenance complex (Mcm2-Mcm7, or Mcm2-7). Several mechanisms of pre-RC regulation are known, including ATP utilization, cyclin-dependent kinase levels, protein turnover, and Cdt1 binding by geminin. Histone acetylation may also affect the initiation of DNA replication, but at present neither the enzymes nor the steps involved are known. Here, we show that Hbo1, a member of the MYST histone acetyltransferase family, is a previously unrecognized positive regulatory factor for pre-RC assembly. When Hbo1 expression was inhibited in human cells, Mcm2-7 failed to associate with chromatin even though ORC and Cdc6 loading was normal. When Xenopus egg extracts were immunodepleted of Xenopus Hbo1 (XHbo1), chromatin binding of Mcm2-7 was lost, and DNA replication was abolished. The binding of Mcm2-7 to chromatin in XHbo1-depleted extracts could be restored by the addition of recombinant Cdt1.

* Corresponding author. Mailing address for M. Mitchell Smith: Department of Microbiology, University of Virginia Health System, P.O. Box 800734, Charlottesville, VA 22908-0734. Phone: (434) 924-2669. Fax: (434) 982-1071. E-mail: mms7r{at}virginia.edu. Mailing address for Haruhiko Takisawa: Department of Biology, Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043, Japan. Phone: 81-6-6850-6762. Fax: 81-6-6850-6762. E-mail: takisawa{at}bio.sci.osaka-u.ac.jp.

{dagger} M.I. and T.M. contributed equally to this work.

Molecular and Cellular Biology, February 2006, p. 1098-1108, Vol. 26, No. 3
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.3.1098-1108.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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