Abstract

The cell's ability to repair damage to its DNA is critical for its survival, and accordingly it has evolved a variety of mechanisms to remove the corruptive alterations to which the genetic material is subject. In addition, in multicellular organisms, maintenance of genomic integrity is critical in successful tumor suppression, and mutant alleles of DNA repair genes have been shown to confer an inherited predisposition to cancer. Compounds that introduce interstrand crosslinks (ICLs) in DNA are both important anticancer agents as well as possible mutagens and carcinogens. However, the mechanisms of repair of these lesions in mammalian cells are poorly understood. Using biochemical approaches we have identified a number of proteins that are required for processing of psoralen ICLs in vitro. These proteins include Ercc1, Xpf, Msh2, Msh3, RPA , and PCNA. The goals of this proposal are to extend our biochemical studies to the identification of additional factors that are required for processing psoralen ICLs in vitro, to determine if the in vitro processing of other classes of ICLs is mediated by the same or different components, and to determine the relevance of the observed in vitro processing of ICLs by directly monitoring their removal in vivo.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA075160-06
Application #
6798747
Study Section
Radiation Study Section (RAD)
Program Officer
Pelroy, Richard
Project Start
1998-08-01
Project End
2006-08-30
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
6
Fiscal Year
2004
Total Cost
$302,000
Indirect Cost

  Institution

Name
University of Texas MD Anderson Cancer Center
Department
Genetics
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030

  Publications

Zhang, Nianxiang; Liu, Xiuping; Li, Lei et al. (2007) Double-strand breaks induce homologous recombinational repair of interstrand cross-links via cooperation of MSH2, ERCC1-XPF, REV3, and the Fanconi anemia pathway. DNA Repair (Amst) 6:1670-8
Lu, Xiaoyan; Legerski, Randy J (2007) The Prp19/Pso4 core complex undergoes ubiquitylation and structural alterations in response to DNA damage. Biochem Biophys Res Commun 354:968-74
Zheng, Huyong; Wang, Xin; Legerski, Randy J et al. (2006) Repair of DNA interstrand cross-links: interactions between homology-dependent and homology-independent pathways. DNA Repair (Amst) 5:566-74
Zhang, Nianxiang; Kaur, Ramandeep; Lu, Xiaoyan et al. (2005) The Pso4 mRNA splicing and DNA repair complex interacts with WRN for processing of DNA interstrand cross-links. J Biol Chem 280:40559-67
Lu, Xiaoyan; Zhang, Nianxiang; Vasquez, Karen et al. (2005) Repair of psoralen interstrand cross-links in Xenopus laevis egg extracts is highly mutagenic. Biochem Biophys Res Commun 336:69-75
Zheng, Huyong; Wang, Xin; Warren, Amy J et al. (2003) Nucleotide excision repair- and polymerase eta-mediated error-prone removal of mitomycin C interstrand cross-links. Mol Cell Biol 23:754-61
Zhang, Nianxiang; Lu, Xiaoyan; Legerski, Randy J (2003) Partial reconstitution of human interstrand cross-link repair in vitro: characterization of the roles of RPA and PCNA. Biochem Biophys Res Commun 309:71-8
Zhang, Xiaoshan; Richie, Christopher; Legerski, Randy J (2002) Translation of hSNM1 is mediated by an internal ribosome entry site that upregulates expression during mitosis. DNA Repair (Amst) 1:379-90
Zhang, Nianxiang; Lu, Xiaoyan; Zhang, Xiaoshan et al. (2002) hMutSbeta is required for the recognition and uncoupling of psoralen interstrand cross-links in vitro. Mol Cell Biol 22:2388-97
Richie, Christopher T; Peterson, Carolyn; Lu, Tao et al. (2002) hSnm1 colocalizes and physically associates with 53BP1 before and after DNA damage. Mol Cell Biol 22:8635-47

Showing the most recent 10 out of 12 publications