Abstract
Oncogenic p53 mutations (Onc-p53) are frequent in lung and many other solid tumors often associated with chromosome aberrations. Why cells with Onc-p53 develop chromosomal aberrations and whether the abnormalities contribute to tumor growth remain elusive. Evidence in this communication demonstrate for the first time that replication stress induced by Onc-p53 triggers re-copying of DNA replication forks, which generates replication intermediates that cause persistent mitotic aberration and DNA segregation errors. Replication intermediates from re-copied replication forks induced by Onc-p53 activate ATM signaling, which stabilizes Onc-p53, reinforces its ability to upregulate replication factors for sustaining replication stress, thus generating a feedforward cycle accelerating tumor formation. In agreement with this observation our time lapse video microscopy show in real time that persistent mitotic aberration and DNA segregation errors induced by Onc-p53 confer selective growth advantage. Accordingly, human lung tumors with Onc-p53 show selection of cells with mitotic aberration during serial passages. Knock down of active replication forks reduces re-copied fork generation by Onc-p53 and specifically induces apoptotic death of lung cancer cells expressing Onc-p53 in xenograft lung tumors synergistically in cooperation with inhibitors of ATM activation, deselecting cells with Onc-p53 with mitotic errors. This communication reveals a novel mechanism which interconnects replication stress induced by Onc-p53 to its stabilization and ability to generate chromosomal aberration in lung cancer cells that both accelerate tumor growth and serve as a targetable therapeutic vulnerability. These findings will be extremely valuable for tumor-specific treatment of a high percentage of cancer patients with p53 mutation.