A postincision-deficient TFIIH causes replication fork breakage and uncovers alternative Rad51- or Pol32-mediated restart mechanisms.

Homologous recombination is a major double-strand break (DSB) repair mechanism that acts during the S and G2 phases. In contrast, nucleotide excision repair (NER) is a major pathway for the repair of DNA bulky adducts that is unrelated to replication. We show that replication can be strongly disturbed in a ...
specific type of rad3/XPD NER mutant of TFIIH, causing replication fork breakage. In contrast to classical NER-deficient mutations, the S. cerevisiae rad3-102 allele, which has a minimal impact on UV resistance, channels bulky adducts into DSBs. rad3-102 allows Rad1/XPF- and Rad2/XPG-catalyzed DNA incisions but fails to perform postincision steps retaining TFIIH at the damaged site. Broken forks are rescued by MRX-Rad52-Rfc1-dependent recombination via two types of replication restart mechanisms, one being Rad51 dependent and the other Pol32 dependent. Our results define the genetic and molecular hallmarks of replication fork breakage and restart and bring insights to understand specific NER-related human syndromes.
Mesh Terms:
DNA Breaks, Double-Stranded, DNA Helicases, DNA Repair, DNA Repair Enzymes, DNA Replication, DNA, Fungal, DNA-Binding Proteins, DNA-Directed DNA Polymerase, Dose-Response Relationship, Radiation, Endodeoxyribonucleases, Endonucleases, Genomic Instability, Genotype, Humans, Mutation, Phenotype, Rad51 Recombinase, Rad52 DNA Repair and Recombination Protein, Radiation Tolerance, Recombination, Genetic, Replication Protein C, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Time Factors, Transcription Factor TFIIH, Ultraviolet Rays
Mol. Cell
Date: Mar. 12, 2010
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