The exonuclease TREX1 is in the SET complex and acts in concert with NM23-H1 to degrade DNA during granzyme A-mediated cell death

Mol Cell. 2006 Jul 7;23(1):133-42. doi: 10.1016/j.molcel.2006.06.005.

Abstract

Granzyme A (GzmA) activates a caspase-independent cell death pathway with morphological features of apoptosis. Single-stranded DNA damage is initiated when the endonuclease NM23-H1 becomes activated to nick DNA after granzyme A cleaves its inhibitor, SET. SET and NM23-H1 reside in an endoplasmic reticulum-associated complex (the SET complex) that translocates to the nucleus in response to superoxide generation by granzyme A. We now find the 3'-to-5' exonuclease TREX1, but not its close homolog TREX2, in the SET complex. TREX1 binds to SET and colocalizes and translocates with the SET complex. NM23-H1 and TREX1 work in concert to degrade DNA. Silencing NM23-H1 or TREX1 inhibits DNA damage and death of cells treated with perforin (PFN) and granzyme A, but not of cells treated with perforin and granzyme B (GzmB). After granzyme A activates NM23-H1 to make single-stranded nicks, TREX1 removes nucleotides from the nicked 3' end to reduce the possibility of repair by rejoining the nicked ends.

Publication types

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

MeSH terms

  • Cell Death / drug effects*
  • Cell Line, Tumor
  • DNA / metabolism*
  • DNA Damage*
  • Exodeoxyribonucleases / pharmacology
  • Exodeoxyribonucleases / physiology*
  • Gene Silencing
  • Granzymes
  • HeLa Cells
  • Humans
  • K562 Cells
  • Multienzyme Complexes / pharmacology
  • Multienzyme Complexes / physiology
  • NM23 Nucleoside Diphosphate Kinases
  • Nucleoside-Diphosphate Kinase / pharmacology
  • Nucleoside-Diphosphate Kinase / physiology*
  • Phosphoproteins / pharmacology
  • Phosphoproteins / physiology*
  • Serine Endopeptidases / metabolism
  • Serine Endopeptidases / physiology*
  • Substrate Specificity

Substances

  • Multienzyme Complexes
  • NM23 Nucleoside Diphosphate Kinases
  • Phosphoproteins
  • DNA
  • NME1 protein, human
  • Nucleoside-Diphosphate Kinase
  • Exodeoxyribonucleases
  • three prime repair exonuclease 1
  • Granzymes
  • Serine Endopeptidases
  • GZMA protein, human