Research area
DNA Metabolism: From Hereditary Cancer Syndromes to Targeted Therapy
We investigate how inherited mutations in cancer predisposition genes BRCA1,BRCA2, RAD51, RAD51 paralogs, PALB2, and ATM –compromise the protection of replicating DNA and drive hereditary breast, ovarian, pancreatic, and prostate cancers. Using electron microscopy, cryo-EM, and biochemical reconstitution, we identify the molecular vulnerabilities of DNA repair-deficient cancer cells that can be exploited by targeted therapies including PARP inhibitors and POLθ inhibitors, and we develop structural approaches to reclassify variants of uncertain significance in cancer susceptibility genes.
Researcher
Vincenzo Costanzo
Vincenzo Costanzo is Full Professor of General Pathology at the University of Milan and Senior Group Leader at IFOM ETS, where he directs the DNA Metabolism programme. After training at Columbia University and founding his lab at Cancer Research UK’s Clare Hall Laboratories, he moved to IFOM in 2013. An elected EMBO Member and recipient of two ERC grants, his discovery that BRCA2 and RAD51 protect replicating DNA from degradation fundamentally changed our understanding of why BRCA mutation carriers develop cancer and how their tumours respond to therapy.
Team
Antonie Aze (Postdoc), Hervé Técher (Postdoc), Arun M. Kolinjivadi (PhD), Anjali Mann (PhD), Andrea Gnocchi (PhD), Christelle El Kai (PhD), Sina Atashpaz (Postdoc), Vincenzo Sannino (Postdoc).
Photogallery
EM image of replication fork isolated from cells defective for BRCA2 showing a ssDNA gap (arrow) at fork junction (left). A typical reversed fork induced by replicaiton fork stalling (right) (Kolinjivadi et al, Molecular Cell 2017)
EM image of replication fork isolated from cells defective for RAD51 showing ssDNA gaps behid forks (white arrow) at fork junction (black arrow) (Hashimoto et al, NSBM 2010)
Immunofluoresce of H2AX foci in BRCA2-/- cancer cells that were untreated (left columns) or treated with APE1 inhibitor (right panels) (Hanthi et al, Mol Cell 2024)
CryoEM images of RAD51 nucleofilaments bound to single stranded (ss)DNA or double stranded ds(DNA)
CryoEM images of RAD51 nucleofilaments bound to single stranded (ss)DNA containing abasic sites (red) (Hanthi et al, Mol Cell 2024)
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