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


  • eng

Conference Location

  • England