Every day, tens of thousands of DNA bases are damaged in each human cell, and one of the most dangerous breaks—a double-strand break—can lead to cancer if not repaired correctly. This project uses structural molecular biology to reveal, at the atomic level, how cells sense these breaks, signal for repair, and remodel tightly packed DNA to allow access. The researcher will focus on three key steps: the initial sensing and signalling by the ATR/Mec1 kinase, the faithful repair process of homologous recombination via the BRCA2-PALB2-RAD51 complex, and the chromatin remodelling carried out by the INO80 complex. Current understanding of these mechanisms is incomplete, limiting our ability to target them therapeutically. This is fundamental science with no immediate practical application. However, similar work on DNA repair proteins has already underpinned the development of PARP inhibitors, a class of cancer drugs that exploit repair defects in tumours. A deeper, atomic-level understanding of these pathways could reveal new vulnerabilities in cancer cells and inform the design of future treatments that disrupt repair or restore it in genetic disorders.
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DNA fidelity and stability are extremely important for the survival and proper function of any organism. However, tens of thousands of DNA bases are damaged in each human cell every day. One of the most severe types of DNA damage is a DNA double-strand break (DSB). Cells have therefore evolved sophisticated systems to sense, signal and repair this damage. For example, upon formation of a DSB, cells have developed checkpoints to recognize DNA damage and to allow cell cycle arrest in order to coor dinate DNA repair. These signalling cascades are primarily mediated by phosphoinositide 3-kinase-related protein kinases. Among the various repair pathways, homologous recombination (HR) is the most faithful repair mechanism as it restores the precise DNA sequence by utilising a sister chromatid as a template. In eukaryotic cells, the genomic DNA is tightly packed into nucleosomes and chromatin for genomic stability and organisation. Prior to HR and other repair processes, chromatin needs to be remodelled so that damaged DNA can be accessed for repair. DNA damage signalling, DNA damage repair and chromatin remodelling are interconnected and coordinate to accomplish the DNA damage response. In this proposal, I plan to study three key steps in the DSB damage response using structural molecular biology approaches in order to provide mechanistic insights into the DSB damage response, namely sensing and signalling by ATR/Mec1, homologous repair through the BRCA2-PALB2-RAD51 complex and the chromatin remodelling by the INO80 complex.
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