title: Structures of human exonuclease 1 DNA complexes suggest a unified mechanism for nuclease family.
abstract: Human exonuclease 1 (hExo1) plays important roles in DNA repair and recombination processes that maintain genomic integrity. It is a member of the 5' structure-specific nuclease family of exonucleases and endonucleases that includes FEN-1, XPG, and GEN1. We present structures of hExo1 in complex with a DNA substrate, followed by mutagenesis studies, and propose a common mechanism by which this nuclease family recognizes and processes diverse DNA structures. hExo1 induces a sharp bend in the DNA at nicks or gaps. Frayed 5' ends of nicked duplexes resemble flap junctions, unifying the mechanisms of endo- and exonucleolytic processing. Conformational control of a mobile region in the catalytic site suggests a mechanism for allosteric regulation by binding to protein partners. The relative arrangement of substrate binding sites in these enzymes provides an elegant solution to a complex geometrical puzzle of substrate recognition and processing.
authors.affiliation: Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Jillian
authors.initials: J
authors.lastname: Orans
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: McSweeney
authors.forename: Ravi R
authors.initials: RR
authors.lastname: Iyer
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hast
authors.forename: Homme W
authors.initials: HW
authors.lastname: Hellinga
authors.forename: Paul
authors.initials: P
authors.lastname: Modrich
authors.forename: Lorena S
authors.initials: LS
authors.lastname: Beese
mesh_terms: D000595:Amino Acid Sequence; D004247:DNA / Q000378:metabolism*; D045643:DNA Repair Enzymes / Q000737:chemistry* / Q000378:metabolism*; D004720:Endonucleases / Q000235:genetics; D005090:Exodeoxyribonucleases / Q000737:chemistry* / Q000378:metabolism*; D045585:Flap Endonucleases / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016415:Sequence Alignment
chemical_list: D004247:DNA; C114331:EXO1 protein, human; D004720:Endonucleases; D005090:Exodeoxyribonucleases; D045585:Flap Endonucleases; C468317:FEN1 protein, human; D045643:DNA Repair Enzymes