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Mol Cell. 2015 Apr 16;58(2):284-96. doi: 10.1016/j.molcel.2015.03.003. Epub 2015 Apr 9.

Caspase-3 promotes genetic instability and carcinogenesis.

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Department of Dermatology, Duke University Medical Center, Durham, NC 27710, USA.
Department of General Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
Cancer Center, First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, USA.
Department of Dermatology, Duke University Medical Center, Durham, NC 27710, USA; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address:


Apoptosis is typically considered an anti-oncogenic process since caspase activation can promote the elimination of genetically unstable or damaged cells. We report that a central effector of apoptosis, caspase-3, facilitates rather than suppresses chemical- and radiation-induced genetic instability and carcinogenesis. We found that a significant fraction of mammalian cells treated with ionizing radiation can survive despite caspase-3 activation. Moreover, this sublethal activation of caspase-3 promoted persistent DNA damage and oncogenic transformation. In addition, chemically induced skin carcinogenesis was significantly reduced in mice genetically deficient in caspase-3. Furthermore, attenuation of EndoG activity significantly reduced radiation-induced DNA damage and oncogenic transformation, identifying EndoG as a downstream effector of caspase-3 in this pathway. Our findings suggest that rather than acting as a broad inhibitor of carcinogenesis, caspase-3 activation may contribute to genome instability and play a pivotal role in tumor formation following damage.

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