Research Group Pavel Janscak

Keywords

Replication stress, DNA damage, Genomic instability, DNA repair

Summary & Mission statement

The research in our laboratory is centered on defining the molecular mechanisms underlying DNA-repair processes in human cells. A long-term goal of our work is to exploit this knowledge for the development of new therapeutic strategies for the treatment of cancer, which are based on targeting specific DNA-repair pathways with small molecule inhibitors.

Overview

DNA damage is a frequent event in the life of a cell. One of the intrinsic causes of DNA damage is DNA-replication stress, a condition characterized by a global slowdown of the progression of replications forks, which arises upon activation of oncogenes and represents a major source of genomic instability in early stages of tumorigenesis. We are interested in understanding how replication stress gives rise to DNA damage and how cells deal with this pathological condition to preserve genomic stability. Our recent studies provided insights into the molecular mechanism underlying the activation of ATR kinase, a master regulator of the cellular response to replication stress, whose inhibitors can selectively kill p53-negative cancer cells and are currently in phase II clinical trials. Moreover, we have characterized the molecular events involved in the initiation of mitotic prophase-specific DNA-repair synthesis that serves to complete DNA replication of difficult-to-replicate loci such as common fragile sites under conditions of replication stress to prevent chromosome missegregation and accumulation of DNA damage in G1 daughter cells. Ongoing and future studies will address the role of transcription-replication interference in oncogene-induced replication stress and the molecular processes involved in the resolution of conflicts between transcription and replication machineries during S-phase.