The DNA-PKcs/JNK/p53 pathway underlies changes in cell fate decision toward death during DNA replication catastrophe.

ABSTRACT: Exacerbating the DNA replication problems of cancer cells serves as a viable therapeutic approach. Nevertheless, the cytotoxicity of cancer drugs is often hampered by therapy-induced senescence, leading to unfavorable patient outcomes. Here, we employ acute replisome dysfunction in combination with Ataxia telangiectasia and Rad3-related (ATR) inhibition as a strategy to divert senescent cells toward death by triggering DNA replication catastrophe, a form of irreversible replication fork collapse caused by excessive single-stranded DNA (ssDNA) accumulation. RNA-sequencing revealed a distinct set of p53-responsive genes responsible for death. We identify c-Jun N-terminal kinase (JNK) to be essential for augmenting p53-dependent apoptotic programs and inducing pan-nuclear distribution of γH2A

SUBMITTER: Patel JA 

PROVIDER: S-EPMC12188298 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature