Abstract

Checkpoints assure that progression from one cell cycle stage to the next proceeds only after previous events have been completed. The long-term goal is to elucidate the molecular mechanism of checkpoints activated by DNA damage in S phase, which results in down-regulation of DNA synthesis. The hypothesis to be addressed by this proposal is that radiation induces a signal transduction pathway that stalls DNA replication by inactivating factors involved in replication initiation. The goal is to identify the replication machinery targets and use the information gained to define the signal transduction pathway. An SV40 in vitro replication system will be used. All components needed have been purified and the SV40 large T antigen is the only non-cellular component.
The specific aims i nclude: 1) to study the post-translational modification and activity of RP-A; 2) to study the post-translational modification and activity of SV40 T antigen; 3) to study the contribution of ATM, p53 and p21 to signalling that can lead to modifications of RP-A and SV40 T antigen; and 4) to begin to purify novel proteins involved in signalling.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA056706-06
Application #
2894935
Study Section
Radiation Study Section (RAD)
Program Officer
Pelroy, Richard
Project Start
1993-07-01
Project End
2004-06-30
Budget Start
1999-07-01
Budget End
2004-06-30
Support Year
6
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
Thomas Jefferson University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107

  Publications

Wang, Hongyan; Wang, Minli; Wang, Huichen et al. (2005) Complex H2AX phosphorylation patterns by multiple kinases including ATM and DNA-PK in human cells exposed to ionizing radiation and treated with kinase inhibitors. J Cell Physiol 202:492-502
Wang, Huichen; Rosidi, Bustanur; Perrault, Ronel et al. (2005) DNA ligase III as a candidate component of backup pathways of nonhomologous end joining. Cancer Res 65:4020-30
Iliakis, G; Wang, H; Perrault, A R et al. (2004) Mechanisms of DNA double strand break repair and chromosome aberration formation. Cytogenet Genome Res 104:14-20
Perrault, Ronel; Wang, Huichen; Wang, Minli et al. (2004) Backup pathways of NHEJ are suppressed by DNA-PK. J Cell Biochem 92:781-94
Wang, Xiang; Guan, Jun; Hu, Baocheng et al. (2004) Involvement of Hus1 in the chain elongation step of DNA replication after exposure to camptothecin or ionizing radiation. Nucleic Acids Res 32:767-75
Wang, Huichen; Boecker, Wilfried; Wang, Hongyan et al. (2004) Caffeine inhibits homology-directed repair of I-SceI-induced DNA double-strand breaks. Oncogene 23:824-34
Iliakis, George; Wang, Ya; Guan, Jun et al. (2003) DNA damage checkpoint control in cells exposed to ionizing radiation. Oncogene 22:5834-47
Wang, Huichen; Perrault, Ange Ronel; Takeda, Yoshihiko et al. (2003) Biochemical evidence for Ku-independent backup pathways of NHEJ. Nucleic Acids Res 31:5377-88
Wang, Xiang; Khadpe, Jay; Hu, Baocheng et al. (2003) An overactivated ATR/CHK1 pathway is responsible for the prolonged G2 accumulation in irradiated AT cells. J Biol Chem 278:30869-74
Zhou, Xiang-Yang; Wang, Xiang; Hu, Baocheng et al. (2002) An ATM-independent S-phase checkpoint response involves CHK1 pathway. Cancer Res 62:1598-603

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