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.
Pubmed ID: 12628186 RIS Download
Active Transport, Cell Nucleus | Apoptosis | Carbon-Oxygen Lyases | Chromosomal Proteins, Non-Histone | DNA Fragmentation | DNA, Single-Stranded | DNA-(Apurinic or Apyrimidinic Site) Lyase | Deoxyribonucleases | Gene Expression Regulation | Gene Silencing | Genes, Tumor Suppressor | Granzymes | HMGB2 Protein | HeLa Cells | Histone Chaperones | Humans | Immunity, Cellular | Jurkat Cells | K562 Cells | Models, Biological | Monomeric GTP-Binding Proteins | NM23 Nucleoside Diphosphate Kinases | Nuclear Proteins | Nucleoside-Diphosphate Kinase | Nucleosomes | Phosphoproteins | Serine Endopeptidases | T-Lymphocytes, Cytotoxic | Transcription Factors