MAD genes from spindle checkpoints to targeted cancer therapies

Abstract Genomic integrity requires precise chromosome replication and segregation during the cell cycle. Disruptions in this process drive chromosomal instability (CIN), a key factor in tumor evolution and therapeutic resistance. Traditionally, MAD genes, including MAD1L1 and MAD2L1, were categorized as spindle assembly checkpoint components, whereas MAD2L2 was primarily recognized as a DNA repair protein. Increasingly, these genes are recognized as part of an integrated genome surveillance system, driven by shared structures, conformational dynamics, and interconnected regulatory mechanisms. Accordingly, the review redefines the MAD gene family as a coordinated axis for genomic stability, governed by conserved HORMA domains. The unique structural features, conformational plasticity, and protein–protein interaction interfaces of MAD-family proteins present unexplored therapeutic opportunities. Understanding these properties and their interaction networks may reveal cancer-specific vulnerabilities and facilitate the development of selective therapeutic strategies, including approaches to overcome therapeutic resistance, particularly in cancers characterized by high chromosomal instability.