Cancer cells use self-inflicted DNA breaks to evade growth limits imposed by genotoxic stress.
Brian D LarsenJan BenadaPhilip Yuk Kwong YungRyan A V BellGeorge PappasVaclav UrbanJohanna K AhlskogTia Tyrsett KuoPavel JanscakLynn Arthur MegeneySimon J ElsässerJiri BartekClaus Storgaard SørensenPublished in: Science (New York, N.Y.) (2022)
Genotoxic therapy such as radiation serves as a frontline cancer treatment, yet acquired resistance that leads to tumor reoccurrence is frequent. We found that cancer cells maintain viability during irradiation by reversibly increasing genome-wide DNA breaks, thereby limiting premature mitotic progression. We identify caspase-activated DNase (CAD) as the nuclease inflicting these de novo DNA lesions at defined loci, which are in proximity to chromatin-modifying CCCTC-binding factor (CTCF) sites. CAD nuclease activity is governed through phosphorylation by DNA damage response kinases, independent of caspase activity. In turn, loss of CAD activity impairs cell fate decisions, rendering cancer cells vulnerable to radiation-induced DNA double-strand breaks. Our observations highlight a cancer-selective survival adaptation, whereby tumor cells deploy regulated DNA breaks to delimit the detrimental effects of therapy-evoked DNA damage.
Keyphrases
- circulating tumor
- radiation induced
- cell free
- genome wide
- dna damage
- single molecule
- coronary artery disease
- dna damage response
- cell death
- dna methylation
- cell fate
- nucleic acid
- dna repair
- oxidative stress
- stem cells
- squamous cell carcinoma
- papillary thyroid
- living cells
- cell proliferation
- signaling pathway
- heat stress
- cell therapy
- stress induced
- lymph node metastasis
- mesenchymal stem cells
- fluorescent probe
- genome wide association study
- copy number