negative regulation of telomerase RNA reverse transcriptase activity

Definition

Target type: biologicalprocess

Any process that stops, prevents or reduces the frequency, rate or extent of telomerase RNA reverse transcriptase activity. [GO_REF:0000059, GOC:BHF, GOC:BHF_telomere, GOC:nc, GOC:TermGenie, PMID:22633954]

Telomerase is a specialized reverse transcriptase enzyme complex that adds repetitive DNA sequences to the ends of chromosomes, known as telomeres, protecting them from degradation and maintaining genome stability. The activity of telomerase is tightly regulated to prevent uncontrolled cell proliferation and tumorigenesis. Negative regulation of telomerase RNA reverse transcriptase activity involves various mechanisms that decrease telomerase enzyme levels, limit its access to telomere ends, or directly inhibit its catalytic activity. These mechanisms can be broadly categorized as follows:

1. Transcriptional Regulation:
- Decreased transcription of telomerase RNA component (TERC) and telomerase reverse transcriptase (TERT) genes: Transcription factors such as c-Myc, p53, and Sp1 can bind to regulatory elements in the TERC and TERT promoters, suppressing their transcription and ultimately reducing telomerase enzyme levels.

2. Post-Transcriptional Regulation:
- MicroRNA (miRNA) mediated regulation: Specific miRNAs can bind to the 3' untranslated regions (UTRs) of TERC and TERT mRNAs, leading to their degradation or translational repression, thereby decreasing telomerase protein levels.

3. Protein Degradation:
- Ubiquitination and proteasomal degradation: Telomerase subunits, particularly TERT, can be targeted for ubiquitination, a post-translational modification that marks proteins for degradation by the proteasome.

4. Inhibition of Enzyme Activity:
- Competitive inhibition: Certain molecules can compete with telomerase substrates, such as nucleotides, for binding to the active site of the enzyme, thereby reducing its catalytic activity.
- Allosteric regulation: Some proteins can bind to telomerase, causing conformational changes that inhibit its activity without directly competing with substrates.

5. Localization and Accessibility:
- Compartmentalization: Telomerase can be sequestered in specific cellular compartments, limiting its access to telomere ends.
- Chromatin structure: The accessibility of telomere ends to telomerase can be influenced by chromatin structure and modifications, such as histone acetylation and methylation.

These regulatory mechanisms operate in a complex and interconnected manner, ensuring that telomerase activity is tightly controlled and balanced to maintain genomic integrity and cellular homeostasis. Dysregulation of telomerase activity, either through increased or decreased activity, has been implicated in various diseases, including cancer, aging, and developmental disorders.'
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Proteins (1)

Compounds (12)