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.
Chowdhury
Dipanjan
D
CBR Institute for Biomedical Research, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Beresford
Paul J
PJ
Zhu
Pengcheng
P
Zhang
Dong
D
Sung
Jung-Suk
JS
Demple
Bruce
B
Perrino
Fred W
FW
Lieberman
Judy
J
D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage; D005090:Exodeoxyribonucleases / Q000494:pharmacology / Q000502:physiology*; D020868:Gene Silencing; D053804:Granzymes; D006367:HeLa Cells; D006801:Humans; D020014:K562 Cells; D009097:Multienzyme Complexes / Q000494:pharmacology / Q000502:physiology; D054778:NM23 Nucleoside Diphosphate Kinases; D009701:Nucleoside-Diphosphate Kinase / Q000494:pharmacology / Q000502:physiology*; D010750:Phosphoproteins / Q000494:pharmacology / Q000502:physiology*; D012697:Serine Endopeptidases / Q000378:metabolism / Q000502:physiology*; D013379:Substrate Specificity
D009097:Multienzyme Complexes; D054778:NM23 Nucleoside Diphosphate Kinases; D010750:Phosphoproteins; D004247:DNA; C517938:NME1 protein, human; D009701:Nucleoside-Diphosphate Kinase; D005090:Exodeoxyribonucleases; C429526:three prime repair exonuclease 1; D053804:Granzymes; D012697:Serine Endopeptidases; C509212:GZMA protein, human