Structures of human exonuclease 1 DNA complexes suggest a unified mechanism for nuclease family

Cell. 2011 Apr 15;145(2):212-23. doi: 10.1016/j.cell.2011.03.005.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • DNA / metabolism*
  • DNA Repair Enzymes / chemistry*
  • DNA Repair Enzymes / metabolism*
  • Endonucleases / genetics
  • Exodeoxyribonucleases / chemistry*
  • Exodeoxyribonucleases / metabolism*
  • Flap Endonucleases / chemistry
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Sequence Alignment

Substances

  • DNA
  • EXO1 protein, human
  • Endonucleases
  • Exodeoxyribonucleases
  • Flap Endonucleases
  • FEN1 protein, human
  • DNA Repair Enzymes

Associated data

  • PDB/3QE9
  • PDB/3QEA
  • PDB/3QEB