Decoding Cancer-Associated Mutations in DNA Polymerase η through Atomistic Simulations

Journal of Chemical Theory and Computation, vol. 22, pp. 8566–8578

Abstract

DNA polymerases (Pols) are essential enzymes for DNA replication within the cell. However, DNA lesions, such as cyclobutane pyrimidine dimers (CPDs) induced by ultraviolet (UV) radiation, can impair Pols's function and DNA replication. Therefore, the presence of CPDs can, for example, lead to xeroderma pigmentosum variant (XP-V), a rare genetic disorder characterized by an increased risk of skin cancer. Nonetheless, in these situations, specific translesion synthesis (TLS) Pols, such as human DNA polymerase η (Polη), can overcome such lesions, enabling DNA polymerization. That is, Polη prevents the pathological risks associated with CPD-caused DNA replication stalling. Here, we analyzed how a selected set of 8 Polη mutations perturbs its structure, DNA binding, and substrate translocation, thereby altering Polη function, preventing it from bypassing CPDs, thus making them XP-V pathogenic mutations. Leveraging recent structural and clinical data on these pathogenic Polη variants, we elucidated the mechanistic basis for their impairment of Polη's ability to bypass damage. We employed molecular dynamics simulations to examine their effects on Polη in pre- and post-translocation states. Although these residues vary in location and chemical nature, we found that all contributed to reducing DNA anchoring to Polη. In this way, we could identify a unified mechanistic framework for decoding how XP-V pathogenic mutations compromise Polη function by destabilizing the Polη-DNA complex.

Authors 3

1. Alessia Visigalli

   Forschungszentrum Jülich · Italian Institute of Technology

   Affiliation as printed

   Forschungszentrum Jülich GmbH , , ,

   Istituto Italiano di Tecnologia , , Via Enrico Melen 83 , ,

2. Paolo Carloni corresponding Aachen

   RWTH Aachen University · Forschungszentrum Jülich

   Affiliation as printed

   Forschungszentrum Jülich GmbH , , ,

   RWTH Aachen University , , ,

3. Marco De Vivo corresponding

   Italian Institute of Technology

   Affiliation as printed

   Istituto Italiano di Tecnologia , , Via Enrico Melen 83 , ,