Abstract:
:PT-ACRAMTU ([PtCl(en)(ACRAMTU-S)](NO(3))(2), en = ethane-1,2-diamine, ACRAMTU = 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea) is a cytotoxic platinum-acridine conjugate previously shown to form adducts with the N3 endocyclic nitrogen of adenine in the DNA minor groove. This unusual observation and our prior determination of the pronounced 5'-TA/TA base-step affinity of the drug have prompted us to investigate effects of these adducts on DNA minor groove binding proteins. Here, we used electrophoretic mobility shift assays to study the recognition of a PT-ACRAMTU-modified TATA box sequence by TATA-binding protein (TBP). The frequency of PT-ACRAMTU adducts in the minor groove of the TATA box was varied by selective elimination of potential major groove and minor groove binding sites in a 24-bp probe sequence through incorporation of deaza nucleobases. The most dramatic effect on TBP binding was observed in a duplex substituted with 7-deaza-G and 7-deaza-A, which reduced binding by as much as 73% compared to an unplatinated duplex. In contrast, elimination of A-N3 binding sites had no significant effect on TBP binding, suggesting that minor groove adducts of PT-ACRAMTU are the cause of inhibition. This notion was further corroborated by efficient platinum-mediated photo-cross-linking of the drug-modified DNA to TBP. PT-ACRAMTU appears to be the first platinum-based drug capable of targeting DNA sequences critical for transcription initiation. The biological consequences of PT-ACRAMTU's minor groove adducts are discussed.
journal_name
Biochemistryjournal_title
Biochemistryauthors
Budiman ME,Bierbach U,Alexander RWdoi
10.1021/bi050745nsubject
Has Abstractpub_date
2005-08-23 00:00:00pages
11262-8issue
33eissn
0006-2960issn
1520-4995journal_volume
44pub_type
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