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.
Mesh Terms:
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
Cell
Date: Mar. 07, 2003
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