Group Leader: Lajos Haracska
In his HCEMM project (entitled as “New players in the replication of damaged DNA and cancer prevention: ubiquitin-PCNA-binding proteins and their mechanisms of action”), his senior group aims at identifying novel molecular targets on cancer therapy. Stalling of the DNA replication machinery, occurring at the site of DNA damage, is a challenging problem for cells. Error-prone bypass of DNA lesions may cause mutagenesis, and as a consequence, cancer. Error-free bypass, by contrast, keeps mutagenesis and thus cancer frequencies low. The significance of these pathways is indicated by the fact that mutations in several of the genes involved lead to inherited disorders with cancer predisposition. Mono or polyubiquitylation of PCNA, a sliding clamp for the replication complex, governs the various pathways for the replication of damaged DNA such as error-prone or error-free translesion synthesis or error-free template switching. However, little is known about how these pathways are regulated by PCNA ubiquitylation and how the readers of this key posttranslational modification operate. His research group has already pinpointed a family of proteins exhibiting a specialized ubiquitin-binding motif, and their preliminary results show that some of the members can physically and functionally interact with ubiquitin-PCNA and function in the replication of damaged DNA. Their preliminary findings provide a strong ground for the project with the main goal of delineating the function of the selected potential ubiquitin-PCNA-binding proteins in DNA lesion bypass. The work will identify ubiquitin-PCNA-interacting proteins, determine the functional consequences of the interaction, and identify the key enzymatic activities affected. The contribution of the new ubiquitin-PCNA-binding proteins to various DNA damage bypass pathways will be analysed by reconstituted DNA lesion bypass systems using purified proteins and tissue culture-based replication reporter systems. In addition to shedding light on DNA damage bypass, their research has the potential to discover new tumour suppressors and provide novel cancer therapeutic targets.