During replication-coupled DNA interstrand crosslink (ICL) repair, the XPF-ERCC1 endonuclease is required for the incisions that release, or "unhook", ICLs, but the mechanism of ICL unhooking remains largely unknown. Incisions are triggered when the nascent leading strand of a replication fork strikes the ICL Here, we report that while purified XPF-ERCC1 incises simple ICL-containing model replication fork structures, the presence of a nascent leading strand, modelling the effects of replication arrest, inhibits this activity. Strikingly, the addition of the single-stranded DNA (ssDNA)-binding replication protein A (RPA) selectively restores XPF-ERCC1 endonuclease activity on this structure. The 5'-3' exonuclease SNM1A can load from the XPF-ERCC1-RPA-induced incisions and digest past the crosslink to quantitatively complete the unhooking reaction. We postulate that these collaborative activities of XPF-ERCC1, RPA and SNM1A might explain how ICL unhooking is achieved .
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5510000 | PMC |
| http://dx.doi.org/10.15252/embj.201796664 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Molecular architecture and functional dynamics of the pre-incision complex in nucleotide excision repair.
Nat Commun
October 2024
Department of Chemistry, Georgia State University, Atlanta, GA, USA.
Article Synopsis
- * Researchers combined techniques like cryo-electron microscopy (cryo-EM), crosslinking mass spectrometry (XL-MS), and AlphaFold2 predictions to create a model of the NER pre-incision complex (PInC), highlighting how proteins interact during DNA repair.
- * The study reveals new insights into how specific proteins (like TFIIH, XPG, and XPF) coordinate their actions, affects DNA binding, and provides explanations for disease-causing mutations related to xeroderma pigmentosum and Cockayne syndrome.
The Fanconi anemia pathway induces chromothripsis and ecDNA-driven cancer drug resistance.
Cell
October 2024
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address:
Chromothripsis describes the catastrophic shattering of mis-segregated chromosomes trapped within micronuclei. Although micronuclei accumulate DNA double-strand breaks and replication defects throughout interphase, how chromosomes undergo shattering remains unresolved. Using CRISPR-Cas9 screens, we identify a non-canonical role of the Fanconi anemia (FA) pathway as a driver of chromothripsis.
View Article and Find Full Text PDFDoes the XPA-FEN1 Interaction Concern to Nucleotide Excision Repair or Beyond?
Biomolecules
July 2024
Institute of Chemical Biology and Fundamental Medicine, 630090 Novosibirsk, Russia.
Article Synopsis
- * XPA is a key protein in NER, involved in later stages of the repair process, and works alongside the FEN1 enzyme, which is essential for completing newly synthesized DNA strands and also plays a role in base excision repair.
- * Research shows that XPA and FEN1 can form complexes both with and without DNA present, suggesting they interact directly; however, XPA appears to slightly reduce FEN1's activity, indicating a regulatory role in DNA repair processes.
Analysis of cytosine deamination events in excision repair sequencing reads reveals mechanisms of incision site selection in NER.
Nucleic Acids Res
February 2024
School of Molecular Biosciences, Washington State University, Pullman, WA 99164, USA.
Nucleotide excision repair (NER) removes helix-distorting DNA lesions and is therefore critical for genome stability. During NER, DNA is unwound on either side of the lesion and excised, but the rules governing incision site selection, particularly in eukaryotic cells, are unclear. Excision repair-sequencing (XR-seq) sequences excised NER fragments, but analysis has been limited because the lesion location is unknown.
View Article and Find Full Text PDFCellular Responses to Widespread DNA Replication Stress.
Int J Mol Sci
November 2023
Department of Medicine and the Mays Cancer Center, The University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA.
Replicative DNA polymerases are blocked by nearly all types of DNA damage. The resulting DNA replication stress threatens genome stability. DNA replication stress is also caused by depletion of nucleotide pools, DNA polymerase inhibitors, and DNA sequences or structures that are difficult to replicate.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!