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Self-inflicted DNA double-strand breaks sustain tumorigenicity and stemness of cancer cells.


ABSTRACT: 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-?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.

SUBMITTER: Liu X 

PROVIDER: S-EPMC5518870 | biostudies-other | 2017 Jun

REPOSITORIES: biostudies-other

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Self-inflicted DNA double-strand breaks sustain tumorigenicity and stemness of cancer cells.

Liu Xinjian X   Li Fang F   Huang Qian Q   Zhang Zhengxiang Z   Zhou Ling L   Deng Yu Y   Zhou Min M   Fleenor Donald E DE   Wang He H   Kastan Michael B MB   Li Chuan-Yuan CY  

Cell research 20170324 6


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 th  ...[more]

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