Schärer Laboratory

Schärer Laboratory

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Schärer Laboratory

We are an international and interdisciplinary research team focused on the study to the molecular pathways underlying DNA repair and the DNA damage response and its connection to tumorigenesis and cancer therapy. Our research combines biochemical, molecular, cellular structural and biology with organic chemistry and genetics. We study a variety of DNA repair pathways, including nucleotide excision repair (NER) and interstrand crosslink (ICL) repair as well as responses to replication stress and double-strand break (DSB) formation. Our studies aim to elucidate the mechanisms by these pathways prevent tumorigenesis and the inherited genetic disorders xeroderma pigmentosum (XP) and Fanconi anemia (FA) and conversely, how they may be targeted in cancer therapy to target the inherent vulnerabilities of tumors and to improve outcomes of treatment by agents such as cisplatin.

Specific Research Areas
1. Chemical Approaches for Studying DNA Repair Pathways
Studies of DNA repair pathways have greatly benefited from the generation and synthesis of DNA probes, in the form of defined site-specific substrates or specific probes for biochemical and cell biological studies. Our laboratory has been developing new methodology to synthesize chemically defined DNA interstrand crosslinks (ICLs), lesion formed by antitumor agents such as cisplatin or nitrogen mustards. We and many laboratories around the world have used these ICLs to delineate the cellular pathways of ICL repair. We are continuing to develop new synthetic probes for the study of ICL repair and other human DNA repair pathways. We are using these probes extensively to investigate various aspects of DNA repair. One recent focus has been the study of how DNA polymerases interact with structurally diverse ICLs. These studies shed new light on the role of DNA polymerases in ICL repair and insights may be used to design more effective therapeutics based on how their DNA adducts interact with DNA polymerases.

2. Molecular Mechanisms of Human Nucleotide Excision Repair (NER)
NER is the pathway that removes bulky, helix destabilizing DNA lesions formed by UV light, environmental chemicals and cancer chemotherapeutic agents such as cisplatin. NER operates by the dynamic and coordinated action of over 30 proteins to recognize DNA lesions and excise them from the genome as part of an oligonucleotide. We have reconstituted the NER reaction using purified NER proteins and substrates prepared in our lab and are working on assembling stable complexes involved in NER reactions for analysis using biochemical and structural methods. Complemented by cell biological studies, these efforts will enable us to elucidate the mechanisms of dynamic complex assembly and progression through the NER pathway. We are also studying how protein-protein interactions organize the NER machinery, for example focusing on the interactions of XPA scaffold protein with TFIIH, RPA and ERCC1.

3. Mechanistic Basis of Resistance and Diagnostic Tools for Platinum Anticancer Therapy
Cisplatin, carboplatin and oxaliplatin are among the most successful and widely used antitumor agents, yet it is still not known which of the different DNA adducts formed are the most clinically relevant and how various DNA repair pathways contribute to the resistance to therapy. We are developing a mass-spectrometry based approach to detect the levels of various platinum-DNA adducts. We will use this method together with cell biology and genetics to correlate adduct levels with resistance to therapy in model- and tumor cell lines. We are using this approach to understand how cisplatin, carboplatin and oxaliplatin lesions are processed in cells and will develop it into a diagnostic and predictive tool for cisplatin therapy outcomes in the clinic. We will extend this approach to lesions formed by additional clinically important DNA damaging agents.

4. Hijacking Transcription-Coupled Nucleotide Excision Repair for Cancer Therapy
The NER pathway has significant impact on the responsiveness of tumors to DNA damaging drugs, such as cisplatin. High levels of the NER gene ERCC1 are indeed a reliable predictor for resistance to cisplatin treatment. By contrast, precision oncology strategies to specifically target tumors based on the NER status are not available. Using the known, but relatively rarely used, drug trabectedin as a starting point, we will study compounds that can induce breaks in the DNA only in NER-proficient cells. We will explore the specific mechanistic hypothesis for how trabectedin induces double stranded breaks in an NER-dependent fashion and explore how this unique property can be applied to treat tumor cells with elevated levels of DNA repair that are resistant to treatment with drugs, such as cisplatin.

Major research field

Life Science, Biology, Chemistry

Desired field of research

Genomic Integrity, Cancer Biology, Chemical Biology

Research Keywords and Topics

Cancer Chemotherapy
Genomic Integrity
DNA Repair
DNA Damage
Nucleotide Excision Repair
DNA Interstrand Crosslink Repair
Personalized Medicine

Research Publications

Groehler AS, Maratova A, Dao NM, Makhmut A, Schärer OD (2023) Development of Comprehensive Ultraperformance Liquid Chromatography-High Resolution Mass Spectrometry Assays to Quantitate Cisplatin-Induced DNA-DNA Cross-Links. Chem Res Tox, published online on May 19, 2023, as

van den Heuvel D., Kim M, Witkamp M, Lambregtse F, Kim HS, ... , Schärer OD*, Luijsterburg MS* (2023) A disease associated XPA allele interferes with TFIIH binding and primarily affect the transcription-coupled sub-pathway of nucleotide excision repair. Proc Natl Acad Sci USA, 120, e2208860120. *Joint corresponding authors

Kim M, Kim HS, D’Souza A, Gallagher K, Jeong E, Topolska-Wos A, ... , Yeo JE, Chazin WJ, Schärer OD (2022), Two Interaction Surfaces Between XPA and RPA Organize the Preincision Complex in Nucleotide Excision Repair. Proc Natl Acad Sci USA 119, e2207408119


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