The intersection of homologous recombination (HR) and mismatch repair (MMR) pathways in DNA repair-defective tumors
Lorena Incorvaia, Tancredi Didier Bazan Russo, Valerio Gristina, Alessandro Perez, Chiara Brando, Clarissa Mujacic, Emilia Di Giovanni, Marco Bono, Silvia Contino, Carla Ferrante Bannera, Maria Concetta Vitale, Andrea Gottardo, Marta Peri, Antonio Galvano, Daniele Fanale, Giuseppe Badalamenti, Antonio Russo, Viviana Bazan
Abstract
Homologous recombination (HR) and mismatch repair (MMR) defects are driver mutational imprints and actionable biomarkers in DNA repair-defective tumors. Although usually thought as mutually exclusive pathways, recent preclinical and clinical research provide preliminary evidence of a functional crosslink and crosstalk between HRR and MMR. Shared core proteins are identified as key players in both pathways, broadening the concept of DNA repair mechanism exclusivity in specific tumor types. These observations may result in unexplored forms of synthetic lethality or hypermutable tumor phenotypes, potentially impacting the cancer risk management, and considerably expanding in the future the therapeutic window for DNA repair-defective tumors.