Telomere Length Homeostasis Responds to Changes in Intracellular dNTP Pools

Genetics - Tập 193 Số 4 - Trang 1095-1105 - 2013
Amitabha Gupta1, Sushma Sharma2, Patrick Reichenbach3, Lisette Marjavaara2, Agneta Nilsson2, Joachim Lingner3, Andrei Chabes2,4, Rodney Rothstein5, Michael Chang5,6
1Department of Cellular, Molecular and Biophysical Studies, Columbia University Medical Center, New York, New York 10032
2Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden
3Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Frontiers in Genetics National Center of Competence in Research, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland
4Laboratory for Molecular Infection Medicine Sweden, Umeå University, SE 901 87 Umeå, Sweden
5Department of Genetics and Development, Columbia University Medical Center, New York, New York 10032
6European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, 9713 AV Groningen, The Netherlands

Tóm tắt

Abstract Telomeres, the ends of linear eukaryotic chromosomes, shorten due to incomplete DNA replication and nucleolytic degradation. Cells counteract this shortening by employing a specialized reverse transcriptase called telomerase, which uses deoxyribonucleoside triphosphates (dNTPs) to extend telomeres. Intracellular dNTP levels are tightly regulated, and perturbation of these levels is known to affect DNA synthesis. We examined whether altering the levels of the dNTP pools or changing the relative ratios of the four dNTPs in Saccharomyces cerevisiae would affect the length of the telomeres. Lowering dNTP levels leads to a modest shortening of telomeres, while increasing dNTP pools has no significant effect on telomere length. Strikingly, altering the ratio of the four dNTPs dramatically affects telomere length homeostasis, both positively and negatively. Specifically, we find that intracellular deoxyguanosine triphosphate (dGTP) levels positively correlate with both telomere length and telomerase nucleotide addition processivity in vivo. Our findings are consistent with in vitro data showing dGTP-dependent stimulation of telomerase activity in multiple organisms and suggest that telomerase activity is modulated in vivo by dGTP levels.

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Genetics

Tập 193 Số 4

1095-1105

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