Research
Research
Overview
DNA and chromosome transactions safeguarding genome integrity
Genome integrity is maintained by a finely tuned network of processes that span from the onset of DNA replication to the faithful segregation of chromosomes. A core set of evolutionarily conserved replisome-associated factors orchestrate the interplay between DNA replication, recombination, and sister chromatid cohesion, ensuring that dividing cells inherit stable genomes. Mutations in these factors underlie various genetic disorders and predispose individuals to cancer. But how do cells achieve such extraordinary precision in duplicating and organizing their genomes while preserving integrity?
Our laboratory takes a comprehensive, systems-level approach to uncover how cells replicate DNA accurately, repair damage with minimal mutagenesis, and segregate sister chromatids with fidelity. We focus on three interrelated research themes:
1. Mechanisms of DNA Damage Tolerance During Replication
How do cells tolerate DNA lesions encountered during replication? Which signaling pathways and molecular principles govern the choice between recombination-based versus mutagenic bypass mechanisms? We investigate the regulatory dynamics at the replisome and within chromatin to unravel how DNA damage tolerance is executed and controlled.
2. Coupling of Cohesion and Repair during Replication.
How is sister chromatid cohesion established during DNA replication, and how does this influence replication fork architecture, DNA repair, and transcriptional programs? We dissect the consequences of perturbing the cohesion machinery and explore how cohesion interfaces with broader aspects of genome function, including DNA repair.
3. Roles of SMC Complexes in Chromosome Structure and Genome Surveillance
How do structural maintenance of chromosomes (SMC) proteins contribute to genome organization, DNA repair, and transcriptional control throughout the cell cycle? We investigate how these complexes influence the persistence of topological DNA structures, chromatid organization and gene expression, focusing on their genomic localization and dynamic behavior.
By integrating these lines of research, we aim to illuminate the fundamental principles that safeguard genome integrity—insights that hold broad relevance for understanding the molecular basis of human disease and for advancing therapeutic strategies in cancer.
Experimental Approaches
We harness the complementary strengths of budding yeast and mammalian model systems to address fundamental questions in cell biology. Leveraging the robust genetic, biochemical, and molecular toolkit available in Saccharomyces cerevisiae, we uncover conserved principles that govern genome maintenance. In parallel, we use vertebrate and mammalian systems to investigate protein dynamics, dissect the function of mammalian-specific paralogues, and study proteins lacking yeast orthologs—thus bridging evolutionary insights with human relevance.
Our experimental toolkit includes:
- Functional genetics and large-scale genetic screens
to identify key players in genome replication, repair, and cell division. - Genome-wide approaches
to profile protein localization, gene expression, and 3D genome architecture. - 2D gel electrophoresis
for high-resolution mapping of DNA replication and repair intermediates. - Transmission electron microscopy (TEM)
to visualize replication structures and DNA repair intermediates at ultrastructural resolution. - Single-molecule assays
enabling detailed analysis of replication dynamics and fork behavior. - Advanced fluorescence microscopy
including protein foci visualization and time-lapse imaging of cell division in real time. - Cell-based assays
to assess sensitivity to genotoxic agents and probe pathway functionality in vivo.
Together, these approaches empower us to dissect the mechanisms safeguarding genome integrity across eukaryotes—from molecular events at the replication fork to their consequences for genome architecture and cell fate.
Research Projects
CRC 1430 "Molecular Mechanisms of Cell State Transitions"
CRC1430 Associate:
DNA helicase Chl1/DDX11 at the intersection of DNA repair and sister chromatid cohesion.