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Molecular and Cellular Biology, July 2003, p. 5005-5017, Vol. 23, No. 14
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.14.5005-5017.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Characterization of a Novel Origin Recognition Complex-Like Complex: Implications for DNA Recognition, Cell Cycle Control, and Locus-Specific Gene Amplification

Mohammad Mohammad, Randall D. York,{dagger} Jonathan Hommel,{ddagger} and Geoffrey M. Kapler*

Department of Medical Biochemistry and Genetics, Texas A&M Health Science Center, College Station, Texas 77843-1114

Received 17 January 2003/ Returned for modification 14 March 2003/ Accepted 17 April 2003

The origin recognition complex (ORC) plays a central role in eukaryotic DNA replication. Here we describe a unique ORC-like complex in Tetrahymena thermophila, TIF4, which bound in an ATP-dependent manner to sequences required for cell cycle-controlled replication and gene amplification (ribosomal DNA [rDNA] type I elements). TIF4's mode of DNA recognition was distinct from that of other characterized ORCs, as it bound exclusively to single-stranded DNA. In contrast to yeast ORCs, TIF4 DNA binding activity was cell cycle regulated and peaked during S phase, coincident with the redistribution of the Orc2-related subunit, p69, from the cytoplasm to the macronucleus. Origin-binding activity and nuclear p69 immunoreactivity were further regulated during development, where they distinguished replicating from nonreplicating nuclei. Both activities were lost from germ line micronuclei following the programmed arrest of micronuclear replication. Replicating macronuclei stained with Orc2 antibodies throughout development in wild-type cells but failed to do so in the amplification-defective rmm11 mutant. Collectively, these findings indicate that the regulation of TIF4 is intimately tied to the cell cycle and developmentally programmed replication cycles. They further implicate TIF4 in rDNA gene amplification. As type I elements interact with other sequence-specific single-strand breaks (in vitro and in vivo), the dynamic interplay of Orc-like (TIF4) and non-ORC-like proteins with this replication determinant may provide a novel mechanism for regulation.

* Corresponding author. Mailing address: Department of Medical Biochemistry and Genetics, Texas A&M Health Science Center, College Station, TX 77843-1114. Phone: (979) 847-8690. Fax: (979) 847-9481. E-mail: gkapler{at}tamu.edu.

{dagger} Present address: Department of Neuroscience, Case Western Reserve University, Cleveland, OH 44106.

{ddagger} Present address: Graduate School of Biomedical Sciences, University of Texas Southwestern Medical Center, Dallas, Tex.

Molecular and Cellular Biology, July 2003, p. 5005-5017, Vol. 23, No. 14
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.14.5005-5017.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Yakisich, J. S., Sandoval, P. Y., Morrison, T. L., Kapler, G. M. (2006). TIF1 Activates the Intra-S-Phase Checkpoint Response in the Diploid Micronucleus and Amitotic Polyploid Macronucleus of Tetrahymena. Mol. Biol. Cell 17: 5185-5197 [Abstract] [Full Text]  
  • Mullen, J. R., Nallaseth, F. S., Lan, Y. Q., Slagle, C. E., Brill, S. J. (2005). Yeast Rmi1/Nce4 Controls Genome Stability as a Subunit of the Sgs1-Top3 Complex. Mol. Cell. Biol. 25: 4476-4487 [Abstract] [Full Text]  
  • Morrison, T. L., Yakisich, J. S., Cassidy-Hanley, D., Kapler, G. M. (2005). TIF1 Represses rDNA Replication Initiation, but Promotes Normal S Phase Progression and Chromosome Transmission in Tetrahymena. Mol. Biol. Cell 16: 2624-2635 [Abstract] [Full Text]  


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