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.
B-Myb, a highly conserved member of the Myb transcription factor family, is expressed ubiquitously in proliferating cells and controls the cell cycle dependent transcription of G2/M-phase genes. Deregulation of B-Myb has been implicated in oncogenesis and loss of genomic stability. We have identified B-Myb as a novel interaction partner of the Mre11-Rad50-Nbs1 (MRN) complex, a key player in the repair of DNA double strand breaks. We show that B-Myb directly interacts with the Nbs1 subunit of the MRN complex and is recruited transiently to DNA-damage sites. In response to DNA-damage B-Myb is phosphorylated by protein kinase GSK3β and released from the MRN complex. A B-Myb mutant that cannot be phosphorylated by GSK3β disturbs the regulation of pro-mitotic B-Myb target genes and leads to inappropriate mitotic entry in response to DNA-damage. Overall, our work suggests a novel function of B-Myb in the cellular DNA-damage signalling.
- MeSH
- ATM protein metabolismus MeSH
- biologické modely MeSH
- buněčné linie MeSH
- DNA vazebné proteiny chemie metabolismus MeSH
- dvouřetězcové zlomy DNA MeSH
- enzymy opravy DNA chemie metabolismus MeSH
- fosforylace MeSH
- GSK3B metabolismus MeSH
- homologní protein MRE11 chemie metabolismus MeSH
- interakční proteinové domény a motivy MeSH
- jaderné proteiny chemie metabolismus MeSH
- lidé MeSH
- mitóza genetika MeSH
- multiproteinové komplexy metabolismus MeSH
- mutace MeSH
- oprava DNA MeSH
- poškození DNA * MeSH
- proteiny buněčného cyklu chemie genetika metabolismus MeSH
- regulace genové exprese MeSH
- sekvence aminokyselin MeSH
- signální transdukce * MeSH
- trans-aktivátory chemie genetika metabolismus MeSH
- vazba proteinů MeSH
- vazebná místa MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
