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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

Authors

  • Fan Z
  • Beresford PJ
  • Oh DY
  • Zhang D
  • Lieberman J

Journal

Cell

Publication Data

March 7, 2003

Associated Grants

  • Agency: NIAID NIH HHS, Id: AI45587

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