negative regulation of double-stranded telomeric DNA binding

Definition

Target type: biologicalprocess

Any process that stops, prevents or reduces the frequency, rate or extent of double-stranded telomeric DNA binding. [GO_REF:0000059, GOC:BHF, GOC:BHF_telomere, GOC:nc, GOC:TermGenie, PMID:18812185]

Negative regulation of double-stranded telomeric DNA binding is a crucial biological process that safeguards genome stability and prevents uncontrolled cell proliferation. Telomeres, located at the ends of chromosomes, are specialized DNA-protein structures that protect the integrity of the genome. They consist of repetitive DNA sequences and associated proteins that shield the chromosome ends from degradation and fusion.

Double-stranded telomeric DNA binding proteins, such as TRF1 and TRF2, are essential components of the telomere complex. These proteins play a vital role in maintaining telomere length and structure, ensuring proper replication and preventing the activation of DNA damage response pathways.

However, excessive telomere binding can lead to telomere dysfunction and cellular senescence. Therefore, negative regulation of double-stranded telomeric DNA binding is essential to maintain telomere homeostasis.

Several mechanisms contribute to this negative regulation:

**1. Competitive Binding:** Proteins that compete with TRF1 and TRF2 for telomeric DNA binding can reduce the affinity of these proteins, thereby modulating their activity. For instance, the protein RAP1 can bind to telomeric DNA, displacing TRF1 and influencing telomere length regulation.

**2. Post-Translational Modifications:** Modifications such as phosphorylation, ubiquitination, and acetylation can alter the activity of telomeric binding proteins. These modifications can affect their ability to bind DNA, interact with other proteins, or undergo degradation. For example, phosphorylation of TRF1 has been linked to increased telomere shortening.

**3. Protein Degradation:** Specific proteases, such as the ubiquitin-proteasome system, can target telomeric binding proteins for degradation, reducing their abundance at telomeres. This mechanism helps to fine-tune telomere length and prevent excessive binding.

**4. Nucleosome Positioning:** The arrangement of nucleosomes, the basic building blocks of chromatin, can influence telomere accessibility and the binding of telomeric proteins. Changes in nucleosome positioning can modulate the binding of TRF1 and TRF2.

**5. RNA-based Regulation:** Non-coding RNAs, such as telomeric repeat-containing RNA (TERRA), can interact with telomeric DNA and influence the binding of telomeric proteins. TERRA has been shown to interfere with TRF1 binding, contributing to telomere uncapping.

The intricate interplay of these mechanisms ensures that telomere binding is tightly controlled, preventing excessive telomere shortening or inappropriate telomere lengthening. Disruptions in negative regulation of double-stranded telomeric DNA binding can lead to various pathologies, including premature aging, cancer, and genomic instability. Understanding these regulatory processes is crucial for developing strategies to address diseases linked to telomere dysfunction.'
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Proteins (1)

Compounds (2)