Alessandro Costa : Architecture and Dynamics of Macromolecular Machines

Goals

A hallmark of cancer cells is genomic instability, arising from errors in the mechanisms that maintain gene copy number and chromosome ploidy. Our research aims to understand how macromolecular machines involved in the activation of DNA replication origins and the progression of the replication fork function to preserve chromosome integrity. To address these issues, we employ a combination of single particle electron microscopy, molecular modelling and biochemistry, to generate mechanistic models that explain the basis of key nucleic acid transactions; for example, we are interested in understanding how replicative helicases collaborate with leading strand polymerases to couple DNA unwinding with DNA synthesis. By describing the architecture and dynamics of the DNA replication machinery, we seek to establish a molecular framework that explains how higher eukaryotes respond to DNA damage and how cell proliferation is regulated to avoid tumorigenesis.