negative regulation of DNA repair

Definition

Target type: biologicalprocess

Any process that stops, prevents, or reduces the frequency, rate or extent of DNA repair. [GOC:go_curators]

Negative regulation of DNA repair involves mechanisms that suppress or inhibit the process of repairing damaged DNA. This intricate process plays a crucial role in maintaining genomic stability and preventing the accumulation of mutations that can lead to various cellular dysfunctions, including cancer.

Here's a detailed breakdown of the biological processes involved:

1. **Signal Sensing and Transduction:** When DNA damage occurs, various sensors detect the damage and initiate signaling pathways. These sensors include proteins like ATM, ATR, and DNA-PKcs. They activate downstream signaling cascades, ultimately leading to the activation of effector molecules.

2. **Suppression of DNA Repair Pathways:** Negative regulation of DNA repair occurs through several mechanisms that directly or indirectly inhibit the activation and function of DNA repair enzymes. These mechanisms include:
* **Inhibition of DNA Repair Enzyme Activity:** Specific proteins can directly bind to and inhibit the activity of DNA repair enzymes, such as DNA polymerases, nucleases, and ligases, hindering their ability to repair damaged DNA.
* **Modulation of DNA Repair Factor Expression:** Negative regulators can suppress the expression of DNA repair genes at the transcriptional or translational level, reducing the availability of essential repair proteins.
* **Alteration of DNA Repair Protein Localization:** Some negative regulators can sequester DNA repair factors in the cytoplasm, preventing their entry into the nucleus where DNA repair takes place.
* **Modification of Chromatin Structure:** Alterations in chromatin structure can hinder the accessibility of damaged DNA to repair enzymes. Negative regulators can influence chromatin remodeling processes, making the DNA less accessible.
* **Induction of Cell Cycle Arrest:** Some negative regulators can induce cell cycle arrest in response to DNA damage, providing time for DNA repair. However, prolonged cell cycle arrest can also contribute to genomic instability.

3. **Impact on Cellular Processes:** Negative regulation of DNA repair has significant consequences for cellular processes:
* **Accumulation of DNA Damage:** Suppressed DNA repair allows for the accumulation of unrepaired DNA damage, which can lead to mutations, genomic instability, and increased risk of cancer development.
* **Cellular Senescence:** Accumulation of DNA damage can trigger cellular senescence, a state of permanent cell cycle arrest, contributing to aging and tissue degeneration.
* **Apoptosis:** In some cases, unrepaired DNA damage can trigger programmed cell death (apoptosis) to eliminate damaged cells and prevent the spread of mutations.

4. **Regulation of Negative Regulation:** The negative regulation of DNA repair is itself tightly regulated, ensuring a balance between DNA repair and other cellular processes. This balance is essential to maintain genomic integrity and prevent uncontrolled cell growth.

5. **Clinical Significance:** Disruption of the negative regulation of DNA repair can contribute to various diseases, including cancer, neurodegenerative disorders, and premature aging. Understanding the intricate mechanisms involved in this process holds potential for developing novel therapeutic strategies for these diseases.'
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Proteins (1)

Compounds (2)