Chromosome Dynamics and Genome Stability
Hamperl LabAbout our Research
We study how DNA replication and transcription can occur simultaneously without major accidents that cause DNA damage and genome instability.
Our genetic information stored in DNA must be accurately expressed, replicated, and maintained to allow cellular proliferation, differentiation, and development in a multicellular organism. How all these processes are coordinated so that they can progress simultaneously on the DNA, free from errors, is poorly understood. Yet the knowledge of the molecular players is essential to uncover how DNA damage and genome instability emerge during the progression of dreadful diseases, such as cancer.
DNA replication and transcription complexes initiate the synthesis of complementary DNA or RNA strands from distinct genomic locations, termed origins and promoters, respectively. Importantly, chromatin presents the natural substrate of these DNA-templated processes. Eukaryotic chromatin is associated, interpreted, and modified by numerous constituents, including DNA and RNA metabolizing machineries, transcription factors, chromatin-modifying proteins, and more. To understand the molecular basis of these DNA transactions, it is critical to define the collective changes of the chromatin structure at the genomic regions where the transcription and replication machineries assemble and drive their biological reactions.
We aim to identify the molecular players and the sequence of events that allow replication and transcription initiation. Our studies will expand our knowledge about how replication timing and gene expression are coordinated in eukaryotic cells and deregulated in a myriad of human disease states.
Once initiated, transcription and replication machineries translocate along the same DNA template, often in opposing directions and at different rates. Mounting evidence suggests that transcription complexes can encounter replication forks on eukaryotic chromosomes. Cells rely on numerous mechanisms to tolerate and resolve such transcription-replication conflicts. The absence of these mechanisms can lead to catastrophic effects on genome stability and cell viability.
We recently established an in vivo system to reconstitute and analyze encounters between the replication fork and a specific type of transcriptional barrier named R-loop in an inducible and localized fashion. Using this system and other cell biological, genetic and proteomic approaches, we aim to elucidate the genetic and epigenetic mechanisms how cells respond, tolerate and resolve different types of transcription-replication conflicts. Our studies will provide insights into how transcription-replication conflicts causes genome instability, often seen during development, in cancer, and many other physiological and disease contexts.
Eukaryotic DNA replication starts at multiple sites throughout the genome and is necessarily coordinated with other chromosomal processes including transcription, chromatin assembly and maturation, recombination and DNA repair. Notably, chromosomes provide the fundamental scaffold for all these dynamic and in part simultaneously occurring processes. Our ultimate goal is to understand the genetic and epigenetic principles of how these fundamental processes are regulated and coordinated to work together on the genome of eukaryotic cells.
We use innovative cell biological, genetic and proteomic approaches in yeast and human cells. We are particularly interested to identify the molecular players and characterize the sequence of events that allow DNA replication and transcription to occur simultaneously on our chromosomes - without major accidents leading to DNA damage and genome instability, a hallmark of cancer and many other human diseases.
DNA replication and transcription complexes initiate the synthesis of complementary DNA or RNA strands from distinct genomic locations, termed origins and promoters, respectively. Importantly, chromatin presents the natural substrate of these DNA-templated processes. Eukaryotic chromatin is associated, interpreted, and modified by numerous constituents, including DNA and RNA metabolizing machineries, transcription factors, chromatin-modifying proteins, and more. To understand the molecular basis of these DNA transactions, it is critical to define the collective changes of the chromatin structure at the genomic regions where the transcription and replication machineries assemble and drive their biological reactions.
We aim to identify the molecular players and the sequence of events that allow replication and transcription initiation. Our studies will expand our knowledge about how replication timing and gene expression are coordinated in eukaryotic cells and deregulated in a myriad of human disease states.
Once initiated, transcription and replication machineries translocate along the same DNA template, often in opposing directions and at different rates. Mounting evidence suggests that transcription complexes can encounter replication forks on eukaryotic chromosomes. Cells rely on numerous mechanisms to tolerate and resolve such transcription-replication conflicts. The absence of these mechanisms can lead to catastrophic effects on genome stability and cell viability.
We recently established an in vivo system to reconstitute and analyze encounters between the replication fork and a specific type of transcriptional barrier named R-loop in an inducible and localized fashion. Using this system and other cell biological, genetic and proteomic approaches, we aim to elucidate the genetic and epigenetic mechanisms how cells respond, tolerate and resolve different types of transcription-replication conflicts. Our studies will provide insights into how transcription-replication conflicts causes genome instability, often seen during development, in cancer, and many other physiological and disease contexts.
Eukaryotic DNA replication starts at multiple sites throughout the genome and is necessarily coordinated with other chromosomal processes including transcription, chromatin assembly and maturation, recombination and DNA repair. Notably, chromosomes provide the fundamental scaffold for all these dynamic and in part simultaneously occurring processes. Our ultimate goal is to understand the genetic and epigenetic principles of how these fundamental processes are regulated and coordinated to work together on the genome of eukaryotic cells.
We use innovative cell biological, genetic and proteomic approaches in yeast and human cells. We are particularly interested to identify the molecular players and characterize the sequence of events that allow DNA replication and transcription to occur simultaneously on our chromosomes - without major accidents leading to DNA damage and genome instability, a hallmark of cancer and many other human diseases.
The Hamperl Lab
Recent Publications
Read more2024 Editorial in Molecular Cell
A quick restart: RNA polymerase jumping onto post-replicative chromatin.
2023 Scientific Article in Nucleic Acids Research
Single molecule MATAC-seq reveals key determinants of DNA replication origin efficiency.
2023 Scientific Article in Journal of Visualized Experiments
Single-copy gene locus chromatin purification in Saccharomyces cerevisiae.
2023 Scientific Article in Blood
A noncanonical enzymatic function of PIWIL4 maintains genomic integrity and leukemic growth in AML.
2023 Review in Nucleus
Where and when to start: Regulating DNA replication origin activity in eukaryotic genomes.
2023 Scientific Article in Cell Reports
Single-copy locus proteomics of early- and late-firing DNA replication origins identifies a role of Ask1/DASH complex in replication timing control.
2022 Scientific Article in Cell Reports