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Molecular and Cellular Biology, November 2003, p. 8363-8376, Vol. 23, No. 22
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.22.8363-8376.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Human Heterochromatin Protein 1 Isoforms HP1Hs{alpha} and HP1Hsß Interfere with hTERT-Telomere Interactions and Correlate with Changes in Cell Growth and Response to Ionizing Radiation

Girdhar G. Sharma,1 Kyu-kye Hwang,2,{dagger} Raj K. Pandita,1,3 Arun Gupta,1 Sonu Dhar,1,{ddagger} Julie Parenteau,4 Manjula Agarwal,1 Howard J. Worman,2 Raymund J. Wellinger,4 and Tej K. Pandita1*

Washington University School of Medicine, St Louis, Missouri 63108,1 College of Physicians and Surgeons, Columbia University, New York, New York 10032,2 Albert Einstein College of Medicine, Bronx, New York 10461,3 Université de Sherbrooke, Sherbrooke, Quebec J1H 5N4, Canada4

Received 19 March 2003/ Returned for modification 6 May 2003/ Accepted 6 August 2003

Telomeres are associated with the nuclear matrix and are thought to be heterochromatic. We show here that in human cells the overexpression of green fluorescent protein-tagged heterochromatin protein 1 (GFP-HP1) or nontagged HP1 isoforms HP1Hs{alpha} or HP1Hsß, but not HP1Hs{gamma}, results in decreased association of a catalytic unit of telomerase (hTERT) with telomeres. However, reduction of the G overhangs and overall telomere sizes was found in cells overexpressing any of these three proteins. Cells overexpressing HP1Hs{alpha} or HP1Hsß also display a higher frequency of chromosome end-to-end associations and spontaneous chromosomal damage than the parental cells. None of these effects were observed in cells expressing mutants of GFP-{Delta}HP1Hs{alpha}, GFP-{Delta}HP1Hsß, or GFP-{Delta}HP1Hs{gamma} that had their chromodomains deleted. An increase in the cell population doubling time and higher sensitivity to cell killing by ionizing radiation (IR) treatment was also observed for cells overexpressing HP1Hs{alpha} or HP1Hsß. In contrast, cells expressing mutant GFP-{Delta}HP1Hs{alpha} or GFP-{Delta}HP1Hsß showed a decrease in population doubling time and decreased sensitivity to IR compared to the parental cells. The effects on cell doubling times were paralleled by effects on tumorigenicity in mice: overexpression of HP1Hs{alpha} or HP1Hsß suppressed tumorigenicity, whereas expression of mutant HP1Hs{alpha} or HP1Hsß did not. Collectively, the results show that human cells are exquisitely sensitive to the amount of HP1Hs{alpha} or HP1Hsß present, as their overexpression influences telomere stability, population doubling time, radioresistance, and tumorigenicity in a mouse xenograft model. In addition, the isoform-specific effects on telomeres reinforce the notion that telomeres are in a heterochromatinized state.

* Corresponding author. Mailing address: Radiation and Cancer Biology Division, Washington University School of Medicine, 4511 Forest Park, St. Louis, MO 63108. Phone: (314) 747-5461. Fax: (314) 362-9790. E-mail: pandita{at}radonc.wustl.edu.

{dagger} Present address: Applied Genetic Technology Corporation, Alachua, FL 32615.

{ddagger} Present address: University of Pittsburgh, Pittsburgh, PA 15261.

Molecular and Cellular Biology, November 2003, p. 8363-8376, Vol. 23, No. 22
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.22.8363-8376.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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