Last Updated: 7/12/2006

Research Interests
One of the responses of organisms to DNA damage is the transcriptional induction of genes encoding proteins that act to repair the damage or to enhance damage tolerance. In this laboratory we are elucidating the mechanisms involved in damage-responsive transcriptional induction using the PHR1 gene of Saccharomyces cerevisiae as a model system. PHR1 encodes the apoenzyme for a DNA repair enzyme, photolyase. Transcription of PHR1 is induced by a variety of DNA damaging agents including UV, MMS, 4NQO and MNNG. Induction reflects primarily loss of transcriptional repression mediated by a damage-responsive repressor. Current research focuses on identifying the components of this repressor, the regulation of repressor activity, and the role of the repressor in regulating the response to UV and oxidative damage. This work is providing new insights into the integration of diverse stress response pathways that directly affect the processing and tolerance of DNA damage in yeast and perhaps carcinogenesis in higher organisms including humans.

Recent Accomplishments and Honors
During the last 5 years we have:
a. Identified two components of the transcriptional repressor, encoded by the RPH1 and GIS1 genes. RPH1 and GIS1 encode two proteins containing zinc fingers and regions of high homology to Retinoblastoma Binding Protein 2, a protein that in mammalian cells is involved in regulation of transcription by nuclear hormone receptors.
b. Demonstrated that RPH1 and GIS1 regulate the cellular response to certain types of oxidative damage. Using genomic arrays we have found that expression of approximately 350 genes is regulated, directly or indirectly, by RPH1 and GIS1. Many of these genes are involved in maintenance of redox homeostasis in the cell or in the response to multiple diverse stress.
c. Discovered that Rph1 moves out of the nucleus in response to DNA damage as well as in response to changes in the supply of certain nutrients. This provides a molecular link between nutritional status and the ability of cells to tolerate DNA damage and other cellular stresses.
d. Identified proteins that interact physically with Rph1 and Gis1, including a DNA helicase SRS2 that has been implicated in generating or propagating the response to certain types of DNA damage.

Publications
a Jang YK, Wang L, Sancar GB.
RPH1 and GIS1 are damage-responsive repressors of PHR1. Mol Cell Biol. 1999 Nov;19(11):7630-8.

b Vande Berg BJ, Sancar GB.
Evidence for dinucleotide flipping by DNA photolyase.
J Biol Chem. 1998 Aug 7;273(32):20276-84.

c Baer ME, Sancar GB.
The role of conserved amino acids in substrate binding and discrimination by photolyase. J Biol Chem. 1993 Aug 5;268(22):16717-24.

d Sebastian J, Sancar GB.
A damage-responsive DNA binding protein regulates transcription of the yeast DNA repair gene PHR1.
Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11251-5.

e Sebastian J, Kraus B, Sancar GB.
Expression of the yeast PHR1 gene is induced by DNA-damaging agents.
Mol Cell Biol. 1990 Sep;10(9):4630-7.

f Sancar GB, Jorns MS, Payne G, Fluke DJ, Rupert CS, Sancar A.
Action mechanism of Escherichia coli DNA photolyase. III. Photolysis of the enzyme-substrate complex and the absolute action spectrum.
J Biol Chem. 1987 Jan 5;262(1):492-8.

g Sweet DH, Jang YK, Sancar GB.
Role of UME6 in transcriptional regulation of a DNA repair gene in Saccharomyces cerevisiae.
Mol Cell Biol. 1997 Nov;17(11):6223-35.

h Sancar GB, Ferris R, Smith FW, Vandeberg B.
Promoter elements of the PHR1 gene of Saccharomyces cerevisiae and their roles in the response to DNA damage.
Nucleic Acids Res. 1995 Nov 11;23(21):4320-8.

E-mail: Gwendolyn_Sancar@med.unc.edu
Telephone: (919) 966-2077
FAX: (919) 966-2852
Address: 431 Mary Ellen Jones Bldg, CB# 7260 Chapel Hill, NC 27599-7260
URL: www.med.unc.edu/wrkunits/2depts/biochem/sancarg.htm

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