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DNA specificity and biological impac...

Budiman, Michael E.

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DNA specificity and biological impact of a platinum acridinylthiourea conjugate.

Record Type:	Electronic resources : Monograph/item
Title/Author:	DNA specificity and biological impact of a platinum acridinylthiourea conjugate./
Author:	Budiman, Michael E.
Description:	123 p.
Notes:	Source: Dissertation Abstracts International, Volume: 67-02, Section: B, page: 0865.
Contained By:	Dissertation Abstracts International67-02B.
Subject:	Chemistry, Biochemistry. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3207036
ISBN:	9780542565625

DNA specificity and biological impact of a platinum acridinylthiourea conjugate.
Budiman, Michael E.

DNA specificity and biological impact of a platinum acridinylthiourea conjugate. - 123 p.

Source: Dissertation Abstracts International, Volume: 67-02, Section: B, page: 0865.

Thesis (Ph.D.)--Wake Forest University, 2006.

This dissertation focuses on the biological and chemical aspects of a novel platinum-acridinylthiourea conjugate, PT-ACRAMTU. This unique platinum compound is found to break the long-lasting paradigm of DNA-binding platinum compounds in that it modifies adenine in the minor groove. The capacity for minor groove modification lies in the novel design of PT-ACRAMTU itself, which instead of having two leaving groups attached to the platinum has only one leaving group and an intercalator. Interestingly, it has also been shown to possess anti-cancer activity against the human ovarian carcinoma cancer cell line C13*, which is cisplatin resistant. These findings prompted us to investigate how PT-ACRAMTU differs from cisplatin with respect to sequence specificity of platination. Furthermore, we set out to characterize the interactions of several cellular proteins with PT-ACRAMTU-modified DNA.

ISBN: 9780542565625Subjects--Topical Terms:

1017722
Chemistry, Biochemistry.

DNA specificity and biological impact of a platinum acridinylthiourea conjugate.
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020 $a 9780542565625
035 $a (UnM)AAI3207036
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040 $a UnM $c UnM
100 1 $a Budiman, Michael E. $3 1919849
245 1 0 $a DNA specificity and biological impact of a platinum acridinylthiourea conjugate.
300 $a 123 p.
500 $a Source: Dissertation Abstracts International, Volume: 67-02, Section: B, page: 0865.
500 $a Adviser: Rebecca W. Alexander.
502 $a Thesis (Ph.D.)--Wake Forest University, 2006.
520 $a This dissertation focuses on the biological and chemical aspects of a novel platinum-acridinylthiourea conjugate, PT-ACRAMTU. This unique platinum compound is found to break the long-lasting paradigm of DNA-binding platinum compounds in that it modifies adenine in the minor groove. The capacity for minor groove modification lies in the novel design of PT-ACRAMTU itself, which instead of having two leaving groups attached to the platinum has only one leaving group and an intercalator. Interestingly, it has also been shown to possess anti-cancer activity against the human ovarian carcinoma cancer cell line C13*, which is cisplatin resistant. These findings prompted us to investigate how PT-ACRAMTU differs from cisplatin with respect to sequence specificity of platination. Furthermore, we set out to characterize the interactions of several cellular proteins with PT-ACRAMTU-modified DNA.
520 $a In vitro biological studies such as enzymatic cleavage protection and footprinting assays were employed to answer questions regarding sequence preference. Several restriction endonucleases were used to compare cisplatin and PT-ACRAMTU mediated cleavage protection. When platination took place at certain sequences in the DNA, inhibition of cleavage was observed. Following treatment of plasmid DNA with PT-ACRAMTU, linearization by either EcoRI (G↓AATTC) or DraI (TTT↓AAA) was inhibited. To further elucidate the DNA damage profile, RNA transcriptional footprinting was employed. RNA transcriptional footprinting was chosen instead of standard DNA footprinting as the former does not require a denaturing step and because PT-ACRAMTU has been shown to inhibit T7 RNA polymerase-catalyzed in vitro transcription. The footprinting profile of PT-ACRAMTU damage, with modification at 5'-TA, 5'-GA, and 5'-CG, is complementary to cisplatin damage, which occurs at 5'-GG, 5'-GC, and 5'-GA sites. Transcriptional footprinting also reveals that PT-ACRAMTU adduct formation is faster than cisplatin, suggesting that PT-ACRAMTU binding is dictated more by the acridine intercalator than the platinum moiety.
520 $a Alternating TA sequences are critical for transcription initiation of both prokaryotic and eukaryotic genes. The conserved TATA sequence within the eukaryotic RNA polymerase II promoter serves as a binding site for RNA polymerase and transcription factors such as the TATA binding protein (TBP) subunit of transcription factor IIID. (Abstract shortened by UMI.)
590 $a School code: 0248.
650 4 $a Chemistry, Biochemistry. $3 1017722
650 4 $a Chemistry, Pharmaceutical. $3 550957
690 $a 0487
690 $a 0491
710 2 0 $a Wake Forest University. $3 1271680
773 0 $t Dissertation Abstracts International $g 67-02B.
790 1 0 $a Alexander, Rebecca W., $e advisor
790 $a 0248
791 $a Ph.D.
792 $a 2006
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3207036