Journal
EMBO REPORTS
Volume 7, Issue 4, Pages 431-437Publisher
WILEY
DOI: 10.1038/sj.embor.7400622
Keywords
granzyme A; Ku70; DNA repair; cytotoxic T lymphocyte
Categories
Funding
- NHLBI NIH HHS [T32 HL066987] Funding Source: Medline
- NIAID NIH HHS [R01 AI045587, AI45587, R56 AI045587] Funding Source: Medline
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Granzyme A (GzmA) induces caspase- independent cell death with morphological features of apoptosis. Here, we show that GzmA at nanomolar concentrations cleaves Ku70, a key double-strand break repair (DSBR) protein, in target cells. Ku70 is cut after Arg(301), disrupting Ku complex binding to DNA. Cleaving Ku70 facilitates GzmA-mediated cell death, as silencing Ku70 by RNA interference increases DNA damage and cell death by GzmB cluster-deficient cytotoxic T lymphocytes or by GzmA and perforin, whereas Ku70 overexpression has the opposite effect. Ku70 has two known antiapoptotic effects - facilitating DSBR and sequestering bax to prevent its translocation to mitochondria. However, GzmA triggers single-stranded, not double-stranded, DNA damage, and GzmA- induced cell death does not involve bax. Therefore, Ku70 has other antiapoptotic functions in GzmA-induced cell death, which are blocked when GzmA proteolyses Ku70.
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