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

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.
Dipanjan Chowdhury 1,  Paul J Beresford,  Pengcheng Zhu,  Dong Zhang,  Jung-Suk Sung,  Bruce Demple,  Fred W Perrino,  Judy Lieberman
Affiliations

Affiliation

  • 1 CBR Institute for Biomedical Research, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA.
PMID: 16818237 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.

Figures