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J. Biol. Chem., Vol. 278, Issue 33, 31149-31158, August 15, 2003

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Functional Domains of Chicken Mitochondrial Transcription Factor A for the Maintenance of Mitochondrial DNA Copy Number in Lymphoma Cell Line DT40^*

Yuichi Matsushima , Kiyoshi Matsumura , Shoji Ishii , Hidetoshi Inagaki , Tomohiro Suzuki ¶, Yoichi Matsuda ¶ **, Konrad Beck ||  and Yasuo Kitagawa  

From the Graduate Courses for Regulation of Biological Signals, ^¶Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, and ^||Bioscience Center, Nagoya University, Nagoya 464-8601 and the Neuroscience Research Institute, National Institute of Advanced Industrial Science and Technology, Tukuba, Ibaragi, 305-8566, Japan

Nuclear and mitochondrial (mt) forms of chicken mt transcription factor A (c-TFAM) generated by alternative splicing of a gene (c-tfam) were cloned. c-tfam mapped at 6q1.1-q1.2 has similar exon/intron organization as mouse tfam except that the first exons encoding the nuclear and the mt form-specific sequences were positioned oppositely. When cDNA encoding the nuclear form was transiently expressed in chicken lymphoma DT40 cells after tagging at the C terminus with c-Myc, the product was localized into nucleus, whereas the only endogenous mt form of DT40 cells was immunostained exclusively within mitochondria. c-TFAM is most similar to Xenopus (xl-) TFAM in having extended C-terminal regions in addition to two high mobility group (HMG) boxes, a linker region between them, and a C-terminal tail, also found in human and mouse TFAM. Similarities between c- and xl-TFAM are higher in linker and C-terminal regions than in HMG boxes. Disruption of both tfam alleles in DT40 cells prevented proliferation. The tfam⁺/tfam^– cells showed a 50 and 40–60% reduction of mtDNA and its transcripts, respectively. Expression of exogenous wild type c-tfam cDNA in the tfam⁺/tfam^– cells increased mtDNA up to 4-fold in a dose-dependent manner, whereas its transcripts increased only marginally. A deletion mutant lacking the first HMG box lost this activity, whereas only marginal reduction of the activity was observed in a deletion mutant at the second HMG box. Despite the essential role of the C-terminal tail in mtDNA transcription demonstrated in vitro, deletion of c-TFAM at this region reduced the activity of maintenance of the mtDNA level only by 50%. A series of deletion mutant at the tail region suggested stimulatory and suppressive sequences in this region for the maintenance of mtDNA level.

Received for publication, April 11, 2003 , and in revised form, May 15, 2003.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AB021166 and AB059657.

^* This work was supported by Research for the Future Program of the Japan Society for the Promotion of Science (to Y. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** A Japan Society for the Promotion of Science Research fellow.

A visiting researcher supported by the Ministry of Education, Science, Culture, and Sports of Japan.

To whom correspondence should be addressed: Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya-shi 464-8601, Japan. Tel.: 81-52-789-5227; Fax: 81-52-789-4296; E-mail: yasuok{at}agr.nagoya-u.ac.jp.

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