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The telomerase reverse transcriptase regulates chromatin state and DNA damage responses
Kenkichi Masutomi1, Richard Possemato, Judy M Y Wong
1Department of Medical Oncology and Biostatistical Science, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Summary
Suppression of human telomerase reverse transcriptase (hTERT) impairs the DNA damage response. Loss of hTERT affects chromatin configuration, leading to increased radiosensitivity and DNA repair deficiencies.
Area of Science:
- Cellular Biology
- Molecular Biology
- Genetics
Background:
- Telomerase, particularly its catalytic subunit human telomerase reverse transcriptase (hTERT), is known to maintain telomere length and prevent cellular senescence.
- Emerging evidence indicates telomerase has roles beyond telomere maintenance, including dynamic regulation in normal cells and contributions to cancer independently of telomere elongation.
Purpose of the Study:
- To investigate the role of hTERT in the cellular response to DNA double-strand breaks.
- To determine if hTERT affects DNA damage response pathways independently of its telomere maintenance function.
Main Methods:
- Studied the effects of suppressing hTERT expression in cells.
- Assessed cellular response to DNA double-strand breaks using assays for radiosensitivity, DNA repair capacity, and chromosomal integrity.
- Analyzed chromatin configuration in cells with and without hTERT.
Main Results:
- Suppression of hTERT abrogated the cellular response to DNA double-strand breaks.
- Loss of hTERT did not affect short-term telomere integrity but altered chromatin configuration.
- Cells lacking hTERT showed increased radiosensitivity, reduced DNA repair capacity, and chromosomal fragmentation.
Conclusions:
- hTERT plays a critical role in the DNA damage response pathway, independent of its canonical function in telomere maintenance.
- Loss of hTERT function compromises the cell's ability to respond to and repair DNA damage, impacting genomic stability.