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
- Chowdhury D
- Beresford PJ
- Zhu P
- Zhang D
- Sung JS
- Demple B
- Perrino FW
- Lieberman J
July 7, 2006
- Agency: NIAID NIH HHS, Id: AI45587
- Agency: NCI NIH HHS, Id: CA71993
- Agency: NIGMS NIH HHS, Id: GM069962
- Agency: NIGMS NIH HHS, Id: GM40000
- Cell Death
- Cell Line, Tumor
- DNA Damage
- Gene Silencing
- HeLa Cells
- K562 Cells
- Multienzyme Complexes
- NM23 Nucleoside Diphosphate Kinases
- Nucleoside-Diphosphate Kinase
- Serine Endopeptidases
- Substrate Specificity
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