tailieunhanh - Báo cáo khoa học: DNA modification with cisplatin affects sequence-specific DNA binding of p53 and p73 proteins in a target site-dependent manner

Proteins p53 and p73 act as transcription factors in cell cycle control, regu-lation of cell development and⁄or in apoptotic pathways. Both proteins bind to response elements (p53 DNA-binding sites), typically consisting of two copies of a motif RRRCWWGYYY. | ỊFEBS Journal DNA modification with cisplatin affects sequence-specific DNA binding of p53 and p73 proteins in a target site-dependent manner Hana Pivonkova1 Petr Pecinka1 Pavla Ceskova2 and Miroslav Fojta1 1 Institute of Biophysics Academy of Sciences of the Czech Republic Brno Czech Republic 2 Masaryk MemorialCancer Institute Brno Czech Republic Keywords cisplatin DNA damage protein p73 sequence-specific DNA recognition tumor suppressor protein p53 Correspondence M. Fojta Institute of Biophysics Academy of Sciences of the Czech Republic Kralovopolska 135 CZ-612 65 Brno Czech Republic Fax 420 541211293 Tel 420 541517197 E-mail fojta@ Received 25 April2006 revised 18 July 2006 accepted 17 August 2006 doi Proteins p53 and p73 act as transcription factors in cell cycle control regulation of cell development and or in apoptotic pathways. Both proteins bind to response elements p53 DNA-binding sites typically consisting of two copies of a motif RRRCWWGYYY. It has been demonstrated previously that DNA modification with the antitumor drug cisplatin inhibits p53 binding to a synthetic p53 DNA-binding site. Here we demonstrate that the effects of global DNA modification with cisplatin on binding of the p53 or p73 proteins to various p53 DNA-binding sites differed significantly depending on the nucleotide sequence of the given target site. The relative sensitivities of protein-DNA binding to cisplatin DNA treatment correlated with the occurrence of sequence motifs forming stable bifunctional adducts with the drug namely GG and AG doublets within the target sites. Binding of both proteins to mutated p53 DNA-binding sites from which these motifs had been eliminated was only negligibly affected by cisplatin treatment suggesting that formation of the cisplatin adducts within the target sites was primarily responsible for inhibition of the p53 or p73 sequence-specific DNA binding. Distinct effects of cisplatin DNA modification on the .