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Granzyme A, which causes single‐stranded DNA damage, targets the double‐strand break repair protein Ku70
Author(s) -
Zhu Pengcheng,
Zhang Dong,
Chowdhury Dipanjan,
Martinvalet Denis,
Keefe Dennis,
Shi Lianfa,
Lieberman Judy
Publication year - 2006
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.1038/sj.embor.7400622
Subject(s) - ku70 , granzyme a , granzyme , biology , microbiology and biotechnology , dna damage , programmed cell death , dna repair , granzyme b , perforin , apoptosis , cytotoxic t cell , dna , genetics , in vitro
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.