title: PC4 promotes genome stability and DNA repair through binding of ssDNA at DNA damage sites.
abstract: The transcriptional cofactor PC4 is an ancient single-strand DNA (ssDNA)-binding protein that has a homologue in bacteriophage T5 where it is likely the elusive replicative ssDNA-binding protein. We hypothesize that human PC4 has retained functions in ssDNA binding to stabilize replication forks and prevent genome instability in mammalian cells. Here we demonstrate that PC4 is recruited to hydroxyurea (HU)-stalled replication forks, which is dependent on active transcription and its ssDNA-binding ability. Interestingly, we demonstrate that ssDNA binding by PC4 is critical to suppress spontaneous DNA damage and promote cellular survival. PC4 accumulation co-localizes with replication protein A (RPA) at stalled forks and is increased upon RPA depletion, demonstrating compensatory functions in ssDNA binding. Depletion of PC4 not only results in defective resolution of HU-induced DNA damage but also significantly reduces homologous recombination repair efficiency. Altogether, our results indicate that PC4 has similar functions to RPA in binding ssDNA to promote genome stability, especially at sites of replication-transcription collisions.
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: O
authors.initials: O
authors.lastname: Mortusewicz
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: B
authors.initials: B
authors.lastname: Evers
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: T
authors.initials: T
authors.lastname: Helleday
mesh_terms: D002478:Cells, Cultured; D053903:DNA Breaks, Double-Stranded; D053904:DNA Breaks, Single-Stranded; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics; D004277:DNA, Single-Stranded / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D042822:Genomic Instability / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D009154:Mutation; D011485:Protein Binding; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: D004277:DNA, Single-Stranded; D004268:DNA-Binding Proteins; C509201:SUB1 protein, human; D014157:Transcription Factors