Self-inflicted DNA double-strand breaks sustain tumorigenicity and stemness of cancer cells.
Journal Article (Journal Article)
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-κB 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.
Full Text
Duke Authors
Cited Authors
- Liu, X; Li, F; Huang, Q; Zhang, Z; Zhou, L; Deng, Y; Zhou, M; Fleenor, DE; Wang, H; Kastan, MB; Li, C-Y
Published Date
- June 2017
Published In
Volume / Issue
- 27 / 6
Start / End Page
- 764 - 783
PubMed ID
- 28337983
Pubmed Central ID
- PMC5518870
Electronic International Standard Serial Number (EISSN)
- 1748-7838
Digital Object Identifier (DOI)
- 10.1038/cr.2017.41
Language
- eng
Conference Location
- England