Abstract

Many different types of DNA-damaging drugs are used as chemotherapeutic agents. The DNA damage caused by these drugs leads to therapeutic effects through as yet incompletely characterized mechanism(s) although inhibition of DNA replication is widely recognized as a potential mechanism. Our goal is to develop paradigms for inhibition of DNA replication caused by DNA-damaging anticancer drugs. The approach utilizes well-defined intracellular Simian Virus 40 and Epstein-Barr Virus DNA to determine whether inhibition of DNA replication by a limited number of DNA-damaging agents with specific and well-characterized mechanisms of action occurs at the level of initiation, elongation or both and whether inhibition occurs via cis or trans mechanisms. Identification of cellular proteins contributing to the inhibition of DNA replication, possibly including those involved in cell cycle checkpoints, will be sought.
The specific aims are as follows:
Aim 1. Characterize DNA-damaging drugs for their ability to inhibit DNA replication a the level of initiation, elongation or both.
Aim 2. Characterize DNA-damaging drugs for their ability to inhibit DNA replication in cis or trans.
Aim 3. Characterize mechanism(s) by which trans-acting DNA-damaging agents inhibit replication.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA077491-03
Application #
6150248
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Program Officer
Lees, Robert G
Project Start
1998-04-01
Project End
2002-01-31
Budget Start
2000-02-01
Budget End
2001-01-31
Support Year
3
Fiscal Year
2000
Total Cost
$288,173
Indirect Cost

  Institution

Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
City
Buffalo
State
NY
Country
United States
Zip Code
14263

  Publications

Tu, Lan Chun; Matsui, Sei Ichi; Beerman, Terry A (2005) Hedamycin, a DNA alkylator, induces (gamma)H2AX and chromosome aberrations: involvement of phosphatidylinositol 3-kinase-related kinases and DNA replication fork movement. Mol Cancer Ther 4:1175-85
Tu, Lan Chun; Melendy, Thomas; Beerman, Terry A (2004) DNA damage responses triggered by a highly cytotoxic monofunctional DNA alkylator, hedamycin, a pluramycin antitumor antibiotic. Mol Cancer Ther 3:577-85
Cao, Pei-rang; McHugh, Mary M; Melendy, Thomas et al. (2003) The DNA minor groove-alkylating cyclopropylpyrroloindole drugs adozelesin and bizelesin induce different DNA damage response pathways in human colon carcinoma HCT116 cells. Mol Cancer Ther 2:651-9
Dziegielewski, Jaroslaw; Beerman, Terry A (2002) Cellular responses to the DNA strand-scission enediyne C-1027 can be independent of ATM, ATR, and DNA-PK kinases. J Biol Chem 277:20549-54
Liu, J S; Kuo, S R; Yin, X et al. (2001) DNA damage by the enediyne C-1027 results in the inhibition of DNA replication by loss of replication protein A function and activation of DNA-dependent protein kinase. Biochemistry 40:14661-8
McHugh, M M; Yin, X; Kuo, S R et al. (2001) The cellular response to DNA damage induced by the enediynes C-1027 and neocarzinostatin includes hyperphosphorylation and increased nuclear retention of replication protein a (RPA) and trans inhibition of DNA replication. Biochemistry 40:4792-9
Dziegielewski, J; Melendy, T; Beerman, T A (2001) Bleomycin-induced alterations in DNA replication: relationship to DNA damage. Biochemistry 40:704-11
Liu, J S; Kuo, S R; McHugh, M M et al. (2000) Adozelesin triggers DNA damage response pathways and arrests SV40 DNA replication through replication protein A inactivation. J Biol Chem 275:1391-7
McHugh, M M; Kuo, S R; Walsh-O'Beirne, M H et al. (1999) Bizelesin, a bifunctional cyclopropylpyrroloindole alkylating agent, inhibits simian virus 40 replication in trans by induction of an inhibitor. Biochemistry 38:11508-15
McHugh, M M; Beerman, T A (1999) C-1027-induced alterations in Epstein-Barr viral DNA replication in latently infected cultured human Raji cells: relationship to DNA damage. Biochemistry 38:6962-70

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