HMGB1 bound to cisplatin-DNA adducts undergoes extensive acetylation and phosphorylation in vivo.

Abstract

Cisplatin, one of the most effective anticancer drugs, is a DNA-damaging agent that induces cell death primarily by apoptosis. For many years, HMGB1 has been known to be a recognition protein for cisplatin-DNA lesions. Here, an application of a biomolecular probe based on a peptide-oligonucleotide conjugate is presented as a novel method for investigating this recognition process in vivo. Proteins known to be involved in the recognition of cisplatin-damaged DNA were pulled down and identified, including members of the HMGB family and a number of other proteins. Interestingly, at least 4 subforms of HMGB1 bind to cisplatin-DNA adducts. These proteins were further identified as post-translationally acetylated or phosphorylated forms of HMGB1. These results provide a rich pool of protein candidates whose roles in the mechanism of action of platinum drugs should be explored. These newly discovered molecular components of the DNA damage signalling cascade could serve as novel links between the initial cell responses to DNA damage and the downstream apoptotic or DNA repair pathways.