What Makes Y Family Pols Potential Candidates for Molecular Targeted Therapies and Novel Biotechnological Applications

Nature has evolved DNA polymerases (Pols) with different replication fidelity with the purpose of maintaining and faithfully propagating the genetic information. Besides the four classical Pols (Pol a, delta, epsilon, gamma), mammalian cells contain at least twelve specialized Pols whose functions have been discovered recently and are still not completely elucidated. Among them, Pols belonging to the Y family contribute to cell survival by promoting DNA damage tolerance. They are primarily involved in the translesion synthesis (TLS) pathway, incorporating dNTPs in an error-free or error-prone manner, depending on the nature of the DNA lesion. From an evolutionary point of view, their high mutagenic potential seems to guarantee the proper flexibility of vital importance for both adaptation to a changeable environment and evolution of the species. These Pols are subjected to a complex network of regulation, since their uncontrolled access to DNA might promote mutagenesis and neoplastic transformation. Altered expression of Y family is a hallmark of several tumor types. In recent years, the unique structure and properties of Y family Pols have been exploited to design molecules that selectively interfere with the Pol of interest with minimal effect on normal cells. In addition, their distinctive properties have been applied to innovative techniques, such as compartmentalized self-replication (CSR), short-patch CSR, phage display and molecular breeding. These approaches are based on mutant Pols provided with novel and ameliorated features and find applications in various fields, from biotechnology to diagnostics, paleontology and forensic analysis.