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

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.

Pubmed ID: 16818237

Authors

  • Chowdhury D
  • Beresford PJ
  • Zhu P
  • Zhang D
  • Sung JS
  • Demple B
  • Perrino FW
  • Lieberman J

Journal

Molecular cell

Publication Data

July 7, 2006

Associated Grants

  • Agency: NIAID NIH HHS, Id: AI45587
  • Agency: NCI NIH HHS, Id: CA71993
  • Agency: NIGMS NIH HHS, Id: GM069962
  • Agency: NIGMS NIH HHS, Id: GM40000

Mesh Terms

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