negative regulation of protection from non-homologous end joining at telomere

Definition

Target type: biologicalprocess

Any process that stops, prevents or reduces the frequency, rate or extent of protection from non-homologous end joining at telomere. [GO_REF:0000058, GOC:BHF, GOC:BHF_telomere, GOC:nc, GOC:TermGenie, PMID:14690602]

Negative regulation of protection from non-homologous end joining at telomere refers to the cellular processes that suppress or hinder the shielding of telomere ends from non-homologous end joining (NHEJ). Telomeres are specialized DNA-protein structures found at the ends of chromosomes. They play a crucial role in maintaining genomic integrity by protecting chromosomes from degradation and fusion during DNA replication.

NHEJ is a major DNA repair pathway that joins broken DNA ends without the need for a homologous template. While essential for repairing double-strand breaks in the genome, NHEJ can be detrimental at telomeres. If left unchecked, NHEJ can lead to telomere fusion, chromosome instability, and cell death.

To prevent this, cells have evolved mechanisms to specifically protect telomeres from NHEJ. These protective mechanisms involve several factors, including:

- **Telomere-specific proteins:** Telomeres are bound by a specialized set of proteins, such as TRF1, TRF2, and POT1, which recognize and bind to the unique DNA sequence at the telomere. These proteins act as a shield, preventing access by NHEJ machinery.
- **Shelterin complex:** The shelterin complex is a multi-protein assembly that forms a protective cap over telomeres. It includes the proteins mentioned above and others that contribute to telomere protection, including RAP1, TPP1, and TIN2.
- **Telomere-specific DNA modifications:** Telomeric DNA is often modified by the addition of specific proteins or chemical modifications that further distinguish telomeres from broken DNA ends, thus avoiding recognition by NHEJ.

Negative regulation of protection from NHEJ at telomeres involves processes that disrupt or weaken these protective mechanisms. This can occur through:

- **Deregulation of telomere-binding proteins:** Mutations or changes in the expression of telomere-binding proteins, such as TRF1 and TRF2, can compromise their ability to shield telomeres from NHEJ.
- **Inhibition of shelterin complex formation:** Factors that interfere with the assembly or stability of the shelterin complex can leave telomeres vulnerable to NHEJ.
- **Removal of telomere-specific modifications:** Changes in the cellular environment or the activity of enzymes responsible for telomere modifications can lead to the loss of these protective marks.

Inhibition of telomere protection from NHEJ can have significant consequences. It can contribute to:

- **Telomere fusion:** NHEJ can join together the ends of two separate chromosomes, leading to chromosome instability.
- **Cellular senescence:** The accumulation of telomere fusions can trigger cell cycle arrest and premature aging.
- **Cancer development:** Loss of telomere protection can promote genomic instability and increase the risk of cancer.

Understanding the intricate interplay between telomere protection mechanisms and NHEJ is crucial for deciphering the cellular processes that maintain genome integrity and prevent disease. Furthermore, investigating the mechanisms of negative regulation of protection from NHEJ at telomeres can offer potential targets for therapeutic intervention in diseases associated with telomere dysfunction.'
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Proteins (2)

Compounds (2)