The broad objective of this proposal is to elucidate the molecular mechanisms involved in transcription-coupled repair (TCR) in mammalian cells of DNA lesions induced by ionizing radiation and other agents that produce oxidative damage. Previous studies have shown that TCR is a discrete pathway for removal of lesions that block transcription and that it directs base excision repair (BER) to oxidative lesions. TCR requires the Cockayne syndrome group B (CSB) protein, the xeroderma pigmentosum group G (XPG) protein and also the XPB and XPD proteins. Examination of different alleles in these genes has revealed that their functions in TCR are separable from their functions in nucleotide excision repair (NER) and that defects in the former are linked to the clinical appearance of the developmental disorder Cockayne syndrome. The overall hypothesis to be tested here are that (a) XPG recruits appropriate repair proteins to lesions that are blocking transcription, and that (b) the intact TCR machinery removes the stalled RNA polymerase (RNAP) to allow repair to occur. Understanding of protein-protein and protein-DNA interactions of XPG will be important for dissecting the multiple functions of this protein and the molecular machine that couples lesion removal to transcription. These studies will advance our understanding of how cells cope with cellular oxidative damage to DNA.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA063503-12
Application #
6835995
Study Section
Radiation Study Section (RAD)
Program Officer
Pelroy, Richard
Project Start
1994-05-19
Project End
2006-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
12
Fiscal Year
2005
Total Cost
$381,685
Indirect Cost
Name
Lawrence Berkeley National Laboratory
Department
Biophysics
Type
Organized Research Units
DUNS #
078576738
City
Berkeley
State
CA
Country
United States
Zip Code
94720
Barnhoorn, Sander; Uittenboogaard, Lieneke M; Jaarsma, Dick et al. (2014) Cell-autonomous progeroid changes in conditional mouse models for repair endonuclease XPG deficiency. PLoS Genet 10:e1004686
Sarker, Altaf H; Chatterjee, Arpita; Williams, Monique et al. (2014) NEIL2 protects against oxidative DNA damage induced by sidestream smoke in human cells. PLoS One 9:e90261
Trego, Kelly S; Chernikova, Sophia B; Davalos, Albert R et al. (2011) The DNA repair endonuclease XPG interacts directly and functionally with the WRN helicase defective in Werner syndrome. Cell Cycle 10:1998-2007
Campeau, Eric; Ruhl, Victoria E; Rodier, Francis et al. (2009) A versatile viral system for expression and depletion of proteins in mammalian cells. PLoS One 4:e6529
Fan, Li; Arvai, Andrew S; Cooper, Priscilla K et al. (2006) Conserved XPB core structure and motifs for DNA unwinding: implications for pathway selection of transcription or excision repair. Mol Cell 22:27-37
Fuss, Jill O; Cooper, Priscilla K (2006) DNA repair: dynamic defenders against cancer and aging. PLoS Biol 4:e203
Perry, J Jefferson P; Yannone, Steven M; Holden, Lauren G et al. (2006) WRN exonuclease structure and molecular mechanism imply an editing role in DNA end processing. Nat Struct Mol Biol 13:414-22
Sarker, Altaf H; Tsutakawa, Susan E; Kostek, Seth et al. (2005) Recognition of RNA polymerase II and transcription bubbles by XPG, CSB, and TFIIH: insights for transcription-coupled repair and Cockayne Syndrome. Mol Cell 20:187-98
Kalogeraki, Virginia S; Tornaletti, Silvia; Cooper, Priscilla K et al. (2005) Comparative TFIIS-mediated transcript cleavage by mammalian RNA polymerase II arrested at a lesion in different transcription systems. DNA Repair (Amst) 4:1075-87
Wang, Jen-Yeu; Sarker, Altaf Hossain; Cooper, Priscilla K et al. (2004) The single-strand DNA binding activity of human PC4 prevents mutagenesis and killing by oxidative DNA damage. Mol Cell Biol 24:6084-93

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