Abstract

Chromosomes serve as the fundamental structural units of our genome, and understanding their proper management is crucial for deciphering disease mechanisms. As a trainee, I delved into the mechanisms that safeguard chromosome ends in mammalian cells, laying the groundwork for my future research endeavors. In my independent laboratory, we have continued to explore essential questions surrounding telomere maintenance and its dysfunction, particularly in relation to cancer. Our research has significantly broadened in scope. For example, we leveraged telomere dysfunction as a strategic tool to unravel the basis of error-prone DNA repair using MMEJ . This approach led to the groundbreaking identification of Polθ, an enzyme pivotal in driving mutagenic repair. Crucially, we discovered that Polθ operates within a salvage pathway in tumors with defective homologous recombination, positioning this polymerase as a promising therapeutic target for cancer treatment. Furthermore, as an independent investigator, I spearheaded a novel research direction focusing on the replication and repair of mitochondrial genomes. This investigation has yielded significant insights, including the elucidation of mechanisms by which toxic mitochondrial DNA (mtDNA) deletions arise. Additionally, we identified a previously unrecognized retrograde signaling pathway that alerts the nucleus to breaks in mtDNA, highlighting a complex interplay between mitochondrial integrity and nuclear responses.