Alessandro Vindigni

Professor of Medicine, Professor of Pathology and Immunology, Professor of Biochemistry and Molecular Biophysics

    • Source: Scopus
    1994 …2021

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    My laboratory focuses on the mechanisms of DNA replication and repair and on the possible strategies to target these mechanisms for cancer treatment. We are one of the few labs worldwide that combines electronic microscopy approaches with genome-wide single-molecule DNA replication assays to study perturbations of replication fork dynamics at single-molecule resolution. Using these technologies, we made substantial contributions to the understanding of the mechanism of replication fork reversal and restart following treatment with cancer chemotherapeutics. We uncovered a key role for the human RECQ1 helicase in the restart of reversed replication forks providing the first insight into the molecular steps that drive the resolution of reverse replication forks. Shortly thereafter, we identified a second human DNA2- and WRN-dependent mechanism of reversed fork processing and restart. We also found that depletion of the central recombinase RAD51 antagonizes this mechanism, presumably by preventing reversed fork formation. Recently, we uncovered a novel function of BRCA proteins in protecting reversed replication fork from nucleolytic degradation. These findings revisit the simplistic view that BRCA protein involvement in replication stress is limited to their role in promoting the HR-mediated repair of DSBs arising at stalled forks. Collectively, our work defined new and important mechanisms for maintaining genome integrity tightly controlled by specific nucleolytic activities and central homologous recombination factors. The environment of my laboratory offers a unique combination of biochemical, cellular, and electron microscopy approaches that is ideal for the training of students and postdoctoral fellows interested in studying the mechanisms responsible for the maintenance of genome integrity. Furthermore, I am currently the Co-Leader of the DNA Metabolism and Repair (DMR) program of the Siteman Cancer Center at Washington University, which provides a unique platform for scientists who work in the closely-related areas of DNA damage response, DNA replication and repair, chromatin biology, and gene regulation.

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