regulation of nucleotide-excision repair

Definition

Target type: biologicalprocess

Any process that modulates the frequency, rate or extent of nucleotide-excision repair. [GOC:jp, PMID:18836076]

Nucleotide-excision repair (NER) is a crucial DNA repair pathway responsible for removing a wide range of bulky DNA lesions, including those induced by ultraviolet (UV) radiation, chemicals, and oxidative damage. This process involves several steps, each catalyzed by specialized proteins, to ensure efficient and accurate repair of damaged DNA.

1. **Damage Recognition:** NER begins with the detection of DNA damage by specific proteins. In eukaryotes, the damage recognition step is mediated by two distinct sub-pathways: global genome repair (GGR) and transcription-coupled repair (TCR).
* **GGR** scans the entire genome for lesions, utilizing a complex of proteins including XPC, RAD23B, and centrin 2. This complex binds to distorted DNA, indicating the presence of damage.
* **TCR** specifically targets lesions that block transcription, employing a complex of RNA polymerase II (RNAPII), CSA, and CSB. This pathway prioritizes the repair of actively transcribed genes, ensuring their continued function.

2. **Damage Verification and Dual Incision:** Once the damage is recognized, a verification step occurs to confirm the presence of a lesion. In GGR, the XPC-RAD23B complex recruits the TFIIH complex, which contains a DNA helicase and a kinase. The helicase unwinds the DNA around the damage, while the kinase phosphorylates XPC, further stabilizing the complex. In TCR, CSA and CSB interact with stalled RNAPII and facilitate recruitment of the TFIIH complex.
* After verification, the TFIIH complex initiates the critical dual incision step. Two endonucleases, XPF-ERCC1 and XPG, are recruited to the damage site. XPF-ERCC1 makes a 5' incision a few nucleotides upstream of the lesion, while XPG makes a 3' incision downstream. This creates a short single-stranded DNA fragment containing the damage.

3. **Excision and Resynthesis:** The damaged DNA fragment is excised by a complex of proteins including the DNA helicase XPD and the 5'-3' exonuclease DNA2. The gap left behind is filled by DNA polymerase using the undamaged strand as a template.

4. **Ligation:** Finally, the newly synthesized DNA strand is joined to the original strand by DNA ligase, completing the repair process.

The regulation of NER is crucial for maintaining genomic integrity and preventing the accumulation of mutations that can lead to cancer and other diseases. Several factors influence NER regulation, including:

* **Transcriptional Control:** The expression levels of NER proteins are regulated by various transcription factors, ensuring their appropriate production in response to DNA damage.
* **Post-Translational Modifications:** NER proteins undergo various modifications, such as phosphorylation and ubiquitination, which influence their activity, stability, and interactions with other proteins.
* **Cellular Stress Responses:** Cells activate specific stress responses, including the DNA damage response pathway, to coordinate NER with other repair pathways and cellular processes.

Understanding the complex mechanisms involved in the regulation of NER is critical for developing strategies to enhance DNA repair and prevent disease. '
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Proteins (6)

Compounds (28)