Mendel-Brno 2000

category image Volume: 17
Issue Number 6, Part 2
June 2000

Recognition of DNA lesions by p53: the role of the C-terminal and core domains

The tumor suppressor protein p53 becomes activated in cells upon various stress conditions including DNA damage. Induced p53 triggers growth arrest or cell death by apoptosis via transcriptional activation of a set of genes containing the consensus p53 binding site and transcriptional repression of another set of genes. In this manner, p53 serves as a gatekeeper which prevents propagation of cells that are at risk of aquiring tumorigenic mutations. Accumulating in vitro and in vivo data suggest that p53 might function also as a caretaker, which preserves genomic integrity by regulating DNA repair. p53 have several biochemical activities which might point to its possible role in DNA repair, involving the recognition of DNA lesions. In the present study we examined the ability of p53 to interact with DNA oligonucleotides mimicking damaged DNA. We show that one unpaired nucleotide within double stranded (ds) DNA was sufficient for recognition by the p53 C-terminus, either as a protruding end or as an internal gap in ds DNA. In contrast, the core domain did not recognize single-stranded (ss) DNA ends or gaps, but interacted with the hairpin structures in ss DNA. The ability of p53 to interact with ss DNA ends and gaps suggests that both single-stranded and double-stranded breaks might serve as a target for the p53 C-terminal interaction in vivo. C-terminal interaction with DNA ends facilitated the core domain binding to DNA, whereas interaction with gaps prevented the core domain/DNA interaction. This implies that p53 might have different mutual positioning of the domains upon binding to ss or ds breaks. One might speculate p53 can recruit different repair factors depending on a type of a lesion and thus facilitate the initial stages of DNA repair.

Marina Protopopova, Sergey B.Zotchev, and Galina Selivanova

Microbiology and Tumor Biology Center,
Karolinska Institutet, S-17177 Stockholm, Sweden.