Publications by authors named "J Marteijn"
Transcription-coupled nucleotide excision repair (TC-NER) efficiently eliminates DNA damage that impedes gene transcription by RNA polymerase II (RNA Pol II). TC-NER is initiated by the recognition of lesion-stalled RNA Pol II by CSB, which recruits the CRL4 ubiquitin ligase and UVSSA. RNA Pol II ubiquitylation at RPB1-K1268 by CRL4 serves as a critical TC-NER checkpoint, governing RNA Pol II stability and initiating DNA damage excision by TFIIH recruitment.
View Article and Find Full Text PDFTranscription-blocking DNA lesions are specifically targeted by transcription-coupled nucleotide excision repair (TC-NER), which removes a broad spectrum of DNA lesions to preserve transcriptional output and thereby cellular homeostasis to counteract aging. TC-NER is initiated by the stalling of RNA polymerase II at DNA lesions, which triggers the assembly of the TC-NER-specific proteins CSA, CSB and UVSSA. CSA, a WD40-repeat containing protein, is the substrate receptor subunit of a cullin-RING ubiquitin ligase complex composed of DDB1, CUL4A/B and RBX1 (CRL4).
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- Voriconazole (VOR), an anti-fungal drug, can cause phototoxicity and skin cancer by impairing the DNA repair process known as nucleotide excision repair (NER).
- VOR affects NER not by changing the expression of related genes but by binding to heterochromatin, disrupting the acetylation of histone H3, which is necessary for effective DNA repair.
- Using histone deacetylase inhibitors to restore H3 acetylation can reverse the NER inhibition caused by VOR, suggesting a potential therapeutic strategy to prevent its harmful effects.
Article Synopsis
- DNA damage disrupts gene transcription by RNA polymerase II, leading to cellular issues, while Transcription-Coupled Nucleotide Excision Repair (TC-NER) helps fix this damage.
- The proteins CSB, CSA, and UVSSA are essential for initiating TC-NER; without them, repair processes fail, leading to different syndromes: UVSS with mild symptoms from UVSSA loss and severe Cockayne Syndrome (CS) from CSA or CSB loss.
- Research shows that in cells lacking CSA or CSB, RNA polymerase II remains stuck at damage sites, hindering repair, while in UVSSA-deficient cells, it is cleared away, allowing alternative repair pathways to function.
Congenital nucleotide excision repair (NER) deficiency gives rise to several cancer-prone and/or progeroid disorders. It is not understood how defects in the same DNA repair pathway cause different disease features and severity. Here, we show that the absence of functional ERCC1-XPF or XPG endonucleases leads to stable and prolonged binding of the transcription/DNA repair factor TFIIH to DNA damage, which correlates with disease severity and induces senescence features in human cells.
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