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

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

Xinjian Liu;Michael B Kastan;Chuan-Yuan Li;Fang Li;Qian Huang;Zhengxiang Zhang;Ling Zhou;Yu Deng;Min Zhou;Donald E Fleenor;He Wang

【期刊名称】《细胞研究（英文版）》 【年(卷),期】2017(027)006

【摘要】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 theit 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 easpases 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