title: G-quadruplex recognition and remodeling by the FANCJ helicase.
abstract: Guanine rich nucleic acid sequences can form G-quadruplex (G4) structures that interfere with DNA replication, repair and RNA transcription. The human FANCJ helicase contributes to maintaining genomic integrity by promoting DNA replication through G4-forming DNA regions. Here, we combined single-molecule and ensemble biochemical analysis to show that FANCJ possesses a G4-specific recognition site. Through this interaction, FANCJ targets G4-containing DNA where its helicase and G4-binding activities enable repeated rounds of stepwise G4-unfolding and refolding. In contrast to other G4-remodeling enzymes, FANCJ partially stabilizes the G-quadruplex. This would preserve the substrate for the REV1 translesion DNA synthesis polymerase to incorporate cytosine across from a replication-stalling G-quadruplex. The residues responsible for G-quadruplex recognition also participate in interaction with MLH1 mismatch-repair protein, suggesting that the FANCJ activity supporting replication and its participation in DNA interstrand crosslink repair and/or heteroduplex rejection are mutually exclusive. Our findings not only describe the mechanism by which FANCJ recognizes G-quadruplexes and mediates their stepwise unfolding, but also explain how FANCJ chooses between supporting DNA repair versus promoting DNA replication through G-rich sequences.
authors.affiliation: Department of Biochemistry, University of Iowa Carver College of Medicine, 51 Newton Rd., 4-532 BSB, Iowa City, IA 52242, USA.
authors.forename: Colin G
authors.initials: CG
authors.lastname: Wu
authors.affiliation: Department of Biochemistry, University of Iowa Carver College of Medicine, 51 Newton Rd., 4-532 BSB, Iowa City, IA 52242, USA maria-spies@uiowa.edu.
authors.forename: Maria
authors.initials: M
authors.lastname: Spies
mesh_terms: D050976:Basic-Leucine Zipper Transcription Factors / Q000737:chemistry* / Q000378:metabolism; D002460:Cell Line; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D004277:DNA, Single-Stranded / Q000737:chemistry / Q000378:metabolism; D051856:Fanconi Anemia Complementation Group Proteins / Q000737:chemistry* / Q000378:metabolism; D054856:G-Quadruplexes; D006801:Humans; D008954:Models, Biological; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D011993:Recombinant Fusion Proteins
chemical_list: C102108:BACH1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D004277:DNA, Single-Stranded; D051856:Fanconi Anemia Complementation Group Proteins; D011993:Recombinant Fusion Proteins; D004247:DNA