S-phase sensing of DNA-protein crosslinks triggers TopBP1-independent ATR activation and p53-mediated cell death by formaldehyde.

ABSTRACT: We examined genotoxic signaling and cell fate decisions in response to a potent DNA-protein crosslinker formaldehyde (FA). DNA-protein crosslinks (DPC) are poorly understood lesions produced by bifunctional carcinogens and several cancer drugs. FA-treated human cells showed a rapid activation of ATR kinase that preferentially targeted the p53 transcription factor at low doses and CHK1 kinase at more severe damage, producing bell-shaped and sublinear responses, respectively. CHK1 phosphorylation was transient, and its loss was accompanied by increased p53 accumulation and Ser15 phosphorylation. Activation of p53 was insensitive to inhibition of mismatch repair and nucleotide and base excision repair, excluding the role of small DNA adducts in this response. The p53-targeted signaling was tr

SUBMITTER: Wong VC 

PROVIDER: S-EPMC3404879 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature