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Molecular and Cellular Biology, December 2005, p. 11073-11088, Vol. 25, No. 24
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.24.11073-11088.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Alterations of DNA and Chromatin Structures at Telomeres and Genetic Instability in Mouse Cells Defective in DNA Polymerase

Mirai Nakamura,¹ Akira Nabetani,¹ Takeshi Mizuno,² Fumio Hanaoka,² and Fuyuki Ishikawa^1*

Laboratory of Cell Cycle Regulation, Department of Gene Mechanisms, Graduate School of Biostudies, Kyoto University, Kitashirakawa-Oiwake-cho, Kyoto 606-8502,¹ Cellular Physiology Laboratory, RIKEN Discovery Research Institute, and SORST, Japan Science and Technology Corporation, Wako, Saitama 351-0198, Japan²

Received 15 August 2005/ Returned for modification 20 September 2005/ Accepted 27 September 2005

Telomere length is controlled by a homeostatic mechanism that involves telomerase, telomere-associated proteins, and conventional replication machinery. Specifically, the coordinated actions of the lagging strand synthesis and telomerase have been argued. Although DNA polymerase , an enzyme important for the lagging strand synthesis, has been indicated to function in telomere metabolism in yeasts and ciliates, it has not been characterized in higher eukaryotes. Here, we investigated the impact of compromised polymerase activity on telomeres, using tsFT20 mouse mutant cells harboring a temperature-sensitive polymerase mutant allele. When polymerase was temperature-inducibly inactivated, we observed sequential events that included an initial extension of the G-tail followed by a marked increase in the overall telomere length occurring in telomerase-independent and -dependent manners, respectively. These alterations of telomeric DNA were accompanied by alterations of telomeric chromatin structures as revealed by quantitative chromatin immunoprecipitation and immunofluorescence analyses of TRF1 and POT1. Unexpectedly, polymerase inhibition resulted in a significantly high incidence of Robertsonian chromosome fusions without noticeable increases in other types of chromosomal aberrations. These results indicate that although DNA polymerase is essential for genome-wide DNA replication, hypomorphic activity leads to a rather specific spectrum of chromosomal abnormality.

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* Corresponding author. Mailing address: Laboratory of Cell Cycle Regulation, Department of Gene Mechanisms, Graduate School of Biostudies, Kyoto University, Kitashirakawa-Oiwake-cho, Kyoto 606-8502, Japan. Phone: 81-75-753-4195. Fax: 81-75-753-4197. E-mail: fishikaw{at}lif.kyoto-u.ac.jp.

Supplemental material for this article may be found at http://mcb.asm.org/.

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Molecular and Cellular Biology, December 2005, p. 11073-11088, Vol. 25, No. 24
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.24.11073-11088.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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