DNA Repair and Epigenomics

Dr. Peter Schmezer

Optimal function of the cellular DNA repair machinery plays a critical role in preserving genomic integrity. Defective or impaired DNA repair increases genomic instability and contributes to malignant transformation.

Genetic and epigenetic repair gene modifications are both contributing to tumor development. Promoter methylation of specific DNA repair genes is an important example how epigenetically silenced targets affect tumor development as well as tumor therapy. There is increasing evidence that

- more repair genes are regulated by epigenetic mechanisms,
- specific repair enzymes are closely cooperating with the DNA methylation-/demethylation machinery, and
- DNA damaging agents can affect epigenetic patterns within the cell nucleus.

• to comprehensively screen human DNA repair genes for promoter hypermethylation and identify new repair genes not yet known to be silenced by methylation

• to elucidate interactions of DNA damage and repair mechanisms with epigenetic gene regulation, especially DNA methylation

• to identify DNA damage-induced (e.g. by ionizing radiation) changes in the DNA methylation patterns

• to identify functional deficiencies in DNA damage response and repair and to elucidate their impact on individual cancer risk, radiosensitivity, therapy outcome and prognosis

• to develop and validate sensitive methods and biomarkers for the characterization of individual DNA repair deficiencies and identification of high risk individuals.

Abbasi R, Ramroth H, Becher H, Dietz A, Schmezer P, Popanda O. Laryngeal cancer risk associated with smoking and alcohol consumption is modified by genetic polymorphisms in ERCC5, ERCC6, and RAD23B but not by polymorphisms in five other nucleotide excision repair genes. Int. J. Cancer 2009, 125:1431-1439

Chang-Claude J, Ambrosone CB, Lilla C, Kropp S, Helmbold I, von Fournier D, Haase W, Sautter-Bihl ML, Wenz F, Schmezer P, Popanda O. Genetic polymorphisms in DNA repair and damage response genes and late normal tissue complications of radiotherapy for breast cancer. British Journal of Cancer 2009, 100:1680-1686

Greve B, Dreffke K, Rickinger A, Könemann S, Fritz E, Eckardt-Schupp F, Amler S, Sauerland C, Braselmann H, Sauter W, Illig T, Schmezer P, Gomolka M, Willich N, Bölling T. Multicentric investigation of ionising radiation-induced cell death as a predictive parameter of individual radiosensitivity. Apoptosis 2009, 14:226-235

Popanda O, Marquardt JU, Chang-Claude J, Schmezer P. Genetic variation in normal tissue toxicity induced by ionizing radiation. Mutation Research / Fundamental and Molecular Mechanisms of Mutagenesis 2009, 667:58-69

Schmezer P, Plass C. Epigenetic aspects in carcinomas of the head and neck. HNO 2008, 56:594-602

Wischermann K, Popp S, Moshir S, Scharfetter-Kochanek K, Wlaschek M, de Gruijl F, Hartschuh W, Greinert R, Volkmer B, Faust A, Rapp A, Schmezer P, Boukamp P. UVA radiation causes DNA strand breaks, chromosomal aberrations and tumorigenic transformation in HaCaT skin keratinocytes. Oncogene 2008, 27:4269-80

Woelfelschneider A, Popanda O, Lilla C, Linseisen J, Mayer C, Celebi O, Debus J, Bartsch H, Chang-Claude J, Schmezer P. A distinct ERCC1 haplotype is associated with mRNA expression levels in prostate cancer patients. Carcinogenesis 2008, 29:1758-64

Sangrajrang S, Schmezer P, Burkholder I, Waas P, Boffetta P, Brennan P, Bartsch H, Wiangnon S, Popanda O. Polymorphisms in three base excision repair genes and breast cancer risk in Thai women. Breast Cancer Res Treat 2008, 111:279-88

Wiebalk K, Schmezer P, Kropp S, Chang-Claude J, Celebi O, Debus J, Bartsch H, Popanda O. In vitro radiation-induced expression of XPC mRNA as a possible biomarker for developing adverse reactions during radiotherapy. Int J Cancer 2007, 21:2340-5

Bartsch H, Dally H, Popanda O, Risch A, Schmezer P. Genetic risk profiles for cancer susceptibility and therapy response. Recent Results Cancer Res 2007, 174:19-36

Popanda O, Edler L, Waas P, Schattenberg T, Butkiewicz D, Muley T, Dienemann H, Risch A, Bartsch H, Schmezer P. Elevated risk of squamous-cell carcinoma of the lung in heavy smokers carrying the variant alleles of the TP53 Arg72Pro and p21 Ser31Arg polymorphisms. Lung Cancer 2007, 55:25-34

Schmezer P, Popanda O. Frühwarnsysteme - genetische Hinweise auf das Krebsrisiko. Krebsforschung heute 2006

Hümmerich J, Werle-Schneider G, Popanda O, Celebi O, Chang-Claude J, Kropp S, Mayer C, Debus J, Bartsch H, Schmezer P. Constitutive mRNA expression of DNA repair-related genes as a biomarker for clinical radio-resistance: A pilot study in prostate cancer patients receiving radiotherapy. Int J Radiat Biol 2006, 82:593-604

Chang-Claude J, Popanda O, Tan XL, Kropp S, Helmbold I, von Fournier D, Haase W, Sautter-Bihl ML, Wenz F, Schmezer P, Ambrosone CB. Association between polymorphisms in the DNA repair genes, XRCC1, APE1, and XPD and acute side effects of radiotherapy in breast cancer patients. Clin Cancer Res 2005, 11:4802-9