Journal
CELL RESEARCH
Volume 27, Issue 6, Pages 764-783Publisher
INST BIOCHEMISTRY & CELL BIOLOGY
DOI: 10.1038/cr.2017.41
Keywords
sublethal caspase activation; spontaneous DNA double-strand breaks; DNA damage response; ATM activation; cancer stem cells
Categories
Funding
- National Institutes of Health [CA155270, ES024015]
- Duke Skin Disease Research Core Center [NIAMS-AR066527]
- National Science Foundation of China (NSFC) [NSFC81120108017, NSFC81572788]
- National Cancer Institute [R01CA157216]
- National Cancer Institute (Duke Cancer Center Support Grant) [P30CA014236]
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DNA double-strand breaks (DSBs) are traditionally associated with cancer through their abilities to cause chromosomal instabilities or gene mutations. Here we report a new class of self-inflicted DNA DSBs that can drive tumor growth irrespective of their effects on genomic stability. We discover a mechanism through which cancer cells cause DSBs in their own genome spontaneously independent of reactive oxygen species or replication stress. In this mechanism, low-level cytochrome c leakage from the mitochondria leads to sublethal activation of apoptotic caspases and nucleases, which causes DNA DSBs. In response to these spontaneous DNA DSBs, ATM, a key factor involved in DNA damage response, is constitutively activated. Activated ATM leads to activation of transcription factors NF kappa B and STAT3, known drivers of tumor growth. Moreover, self-inflicted DNA DSB formation and ATM activation are important in sustaining the stemness of patient-derived glioma cells. In human tumor tissues, elevated levels of activated ATM correlate with poor patient survival. Self-inflicted DNA DSBs therefore are functionally important for maintaining the malignancy of cancer cells.
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