Abstract
Apoptosis and necrosis, two major forms of cell death, can be distinguished morphologically and biochemically. Internucleosomal DNA fragmentation (INDF) is a biochemical hallmark of apoptosis, and caspase-activated DNase (CAD), also known as DNA fragmentation factor 40 kDa (DFF40), is one of the major effector endonucleases. DNase γ, a Mg2+/Ca2+-dependent endonuclease, is also known to generate INDF but its role among other apoptosis-associated endonucleases in cell death is unclear. Here we show that (i) INDF occurs even during necrosis in cell lines, primary cells, and in tissues of mice in vivo, and (ii) DNase γ, but not CAD, is the effector endonuclease for INDF in cells undergoing necrosis. These results document a previously unappreciated role for INDF in necrosis and define its molecular basis.
Highlights
Two cell death patterns, apoptosis and necrosis, can be distinguished from each other morphologically and biochemically [1,2]
A selective role for DNase c in necrosis-associated internucleosomal DNA fragmentation (INDF) To directly compare the role of DNase c in necrosis and apoptosis, we first used the Ramos Burkitt’s lymphoma cell line, which has no DNase c activity, and its derivative cRamos-25 stably expressing exogenous DNase c [19]
The cleavage of poly-ADP ribose polymerase (PARP) from the 116-kDa to the 85-kDa form, a hallmark of apoptosis [20], was induced only by the staurosporine treatment (Fig. 1, bottom). This result suggests a selective role for DNase c in the generation of INDF in necrosis
Summary
Apoptosis and necrosis, can be distinguished from each other morphologically and biochemically [1,2]. Necrosis is evoked by non-physiological stimuli that cause damage to the plasma membrane, and is characterized morphologically by cell swelling and lysis, and biochemically by random digestion of DNA, resulting in a smear on analysis by agarose gel electrophoresis. The necrosis-associated DNA degradation process and its physiological significance, have not been fully elucidated. Apoptosis is characterized morphologically by the formation of membrane-associated apoptotic bodies, membrane blebbing, nuclear breakdown, and chromatin condensation, and biochemically by internucleosomal DNA fragmentation (INDF), appearing as a ladder on agarose gel electrophoresis. INDF, shown as DNA ladder and TUNEL, are widely accepted as the biochemical criterion of apoptosis
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