Repair of chemically distinct DNA lesions
DNA damage is caused by a wide range of chemical agents, including chemotherapeutics, endogenous metabolites, and even microbiome-derived metabolites. Failure to repair DNA damage drives cancer, ageing, and genetic diseases. We are interested in determining how chemically distinct forms of damage are repaired. We engineer DNA substrates with site-specific and chemically-defined DNA lesions and interrogate the repair of these substrates using cell-free extracts produced form the eggs of Xenopus laevis. By elucidating the mechanisms of DNA repair, we aim to understand the molecular basis of human pathologies caused by DNA repair deficiencies. |
Mechanisms of NEIL3- and HMCES-dependent ICL repair
DNA interstrand cross-links (ICLs) are toxic DNA lesions that covalently link that two strands of DNA and block essential processes such as DNA replication. We discovered that ICLs can be repaired by the NEIL3 DNA glycosylase, which cleaves a glycosidic bond in the cross-link and generates a DNA abasic site. Surprisingly, the abasic site in turn reacts with the HMCES protein, converting the lesion into a DNA-protein cross-link that stabilizes the DNA and prevents the formation of DNA double strand breaks. We are now investigating how the activities of NEIL3 and HMCES are regulated and how these proteins contribute DNA repair at a genomic scale. |
Identification of endogenous DNA lesions
Many human genetic diseases are caused by mutations in different DNA repair factors. However, the endogenous damage that drives these pathologies are frequently unknown. We are using mass spectrometry approaches to identify DNA lesions that form spontaneously in cells and determine the frequency of these lesion in different tissue types and different disease states. |
Semlow Lab
Division of Chemistry and Chemical Engineering
California Institute of Technology
1200 E. California Blvd, Pasadena, CA 91125
Division of Chemistry and Chemical Engineering
California Institute of Technology
1200 E. California Blvd, Pasadena, CA 91125