Human Heterochromatin Protein 1 Isoforms HP1Hsα and HP1Hsβ Interfere with hTERT-Telomere Interactions and Correlate with Changes in Cell Growth and Response to Ionizing Radiation

Girdhar G. Sharma, Kyu Kye Hwang, Raj K. Pandita, Arun Gupta, Sonu Dhar, Julie Parenteau, Manjula Agarwal, Howard J. Worman, Raymund J. Wellinger, Tej K. Pandita

Research output: Contribution to journalArticle

78 Scopus citations

Abstract

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 HP1Hsα or HP1Hsβ, but not HP1 Hsγ, 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 HP1Hsα or HP1 Hsβ 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-ΔHP1Hsα, GFP-ΔHP1Hsβ, or GFP-ΔHP1Hsγ 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 HP1Hsα or HP1Hsβ. In contrast, cells expressing mutant GFP-ΔHP1Hsα or GFP-ΔHP1Hsβ 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 HP1Hsα or HP1Hsβ suppressed tumorigenicity, whereas expression of mutant HP1Hsα or HP1 Hsβ did not. Collectively, the results show that human cells are exquisitely sensitive to the amount of HP1Hsα or HP1 Hsβ 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.

Original languageEnglish (US)
Pages (from-to)8363-8376
Number of pages14
JournalMolecular and cellular biology
Volume23
Issue number22
DOIs
StatePublished - Nov 1 2003

    Fingerprint

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Sharma, G. G., Hwang, K. K., Pandita, R. K., Gupta, A., Dhar, S., Parenteau, J., Agarwal, M., Worman, H. J., Wellinger, R. J., & Pandita, T. K. (2003). Human Heterochromatin Protein 1 Isoforms HP1Hsα and HP1Hsβ Interfere with hTERT-Telomere Interactions and Correlate with Changes in Cell Growth and Response to Ionizing Radiation. Molecular and cellular biology, 23(22), 8363-8376. https://doi.org/10.1128/MCB.23.22.8363-8376.2003