Tumor suppressor NM23-H1 is a granzyme A-activated DNase during CTL-mediated apoptosis, and the nucleosome assembly protein SET is its inhibitor.
Granzyme A (GzmA) induces a caspase-independent cell death pathway characterized by single-stranded DNA nicks and other features of apoptosis. A GzmA-activated DNase (GAAD) is in an ER associated complex containing pp32 and the GzmA substrates SET, HMG-2, and Ape1. We show that GAAD is NM23-H1, a nucleoside diphosphate kinase implicated in suppression of tumor metastasis, and its specific inhibitor (IGAAD) is SET. NM23-H1 binds to SET and is released from inhibition by GzmA cleavage of SET. After GzmA loading or CTL attack, SET and NM23-H1 translocate to the nucleus and SET is degraded, allowing NM23-H1 to nick chromosomal DNA. GzmA-treated cells with silenced NM23-H1 expression are resistant to GzmA-mediated DNA damage and cytolysis, while cells overexpressing NM23-H1 are more sensitive.
Fan
Zusen
Z
Center for Blood Research and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Beresford
Paul J
PJ
Oh
David Y
DY
Zhang
Dong
D
Lieberman
Judy
J
D021581:Active Transport, Cell Nucleus / Q000235:genetics*; D017209:Apoptosis / Q000235:genetics*; D019757:Carbon-Oxygen Lyases / Q000235:genetics / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D053938:DNA Fragmentation / Q000235:genetics; D004277:DNA, Single-Stranded / Q000235:genetics / Q000378:metabolism; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D004268:DNA-Binding Proteins; D003851:Deoxyribonucleases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D020868:Gene Silencing / Q000502:physiology; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D053804:Granzymes; D024261:HMGB2 Protein / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D056488:Histone Chaperones; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics*; D019169:Jurkat Cells; D020014:K562 Cells; D008954:Models, Biological; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D054778:NM23 Nucleoside Diphosphate Kinases; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009701:Nucleoside-Diphosphate Kinase; D009707:Nucleosomes / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D002868:Chromosomal Proteins, Non-Histone; D004277:DNA, Single-Stranded; D004268:DNA-Binding Proteins; D024261:HMGB2 Protein; D056488:Histone Chaperones; D054778:NM23 Nucleoside Diphosphate Kinases; D009687:Nuclear Proteins; D009707:Nucleosomes; D010750:Phosphoproteins; C513473:SET protein, human; D014157:Transcription Factors; C517938:NME1 protein, human; D009701:Nucleoside-Diphosphate Kinase; D003851:Deoxyribonucleases; D053804:Granzymes; D012697:Serine Endopeptidases; C509212:GZMA protein, human; D020559:Monomeric GTP-Binding Proteins; D019757:Carbon-Oxygen Lyases; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase