Presented By: Center for RNA Biomedicine
RNA Innovation Seminar: Jeremy Schroeder, Biological Chemistry
RNA:DNA hybrids cause genome instability through nucleobase deamination, genomic rearrangements, and induction of the DNA damage response
HYBRID SEMINAR:
In-person: BSRB, ABC seminar rooms
zoom: https://umich.zoom.us/webinar/register/WN_7NclygHtQZ-I0nC5tQxutg
Abstract:
The overall impacts of naturally occurring RNA:DNA hybrids on genome integrity, and the relative contributions of ribonucleases H to mitigating the negative effects of these hybrids, remain unknown. Here, we use the model bacterium Bacillus subtilis to investigate the contribution of RNases HII (RnhB) and HIII (RnhC) to hybrid removal, DNA replication, and mutagenesis genome-wide. Deletion of either rnhB or rnhC alters RNA:DNA hybrid formation, but with distinct patterns of mutagenesis and hybrid accumulation. For ΔrnhB, hybrids form preferentially in genes transcribed co-directionally with DNA replication. For ΔrnhC, hybrids accumulate in all genes regardless of their orientation, and DNA replication is disrupted leading to transversions and structural variation. We find that base deamination in the displaced strand of an R-loop leads to transition mutations in coding sequences, independent of gene orientation. Our results resolve the outstanding question of how hybrids in native genomic contexts interact with replication to cause mutagenesis.
Bio:
I am a Research Investigator in the Department of Biological Chemistry at University of Michigan. I am interested in how heterogeneity arises in bacterial populations, which has led me to study mechanisms of genome instability and mutagenesis. Mechanisms of mutagenesis have been difficult to understand because multiple factors, such as DNA replication, local sequence context, gene expression, and R-loop abundance converge to influence the mutation rate of a given genomic locus. Natural selection further confounds our understanding of mutagenic mechanisms by effectively masking from observation a subset of mutations that occur. By combining multiple disparate observations of gene expression, R-loop abundance, DNA replication, and mutagenesis, I have assembled the necessary resources to assign roles for several biological processes in mutagenesis.
In-person: BSRB, ABC seminar rooms
zoom: https://umich.zoom.us/webinar/register/WN_7NclygHtQZ-I0nC5tQxutg
Abstract:
The overall impacts of naturally occurring RNA:DNA hybrids on genome integrity, and the relative contributions of ribonucleases H to mitigating the negative effects of these hybrids, remain unknown. Here, we use the model bacterium Bacillus subtilis to investigate the contribution of RNases HII (RnhB) and HIII (RnhC) to hybrid removal, DNA replication, and mutagenesis genome-wide. Deletion of either rnhB or rnhC alters RNA:DNA hybrid formation, but with distinct patterns of mutagenesis and hybrid accumulation. For ΔrnhB, hybrids form preferentially in genes transcribed co-directionally with DNA replication. For ΔrnhC, hybrids accumulate in all genes regardless of their orientation, and DNA replication is disrupted leading to transversions and structural variation. We find that base deamination in the displaced strand of an R-loop leads to transition mutations in coding sequences, independent of gene orientation. Our results resolve the outstanding question of how hybrids in native genomic contexts interact with replication to cause mutagenesis.
Bio:
I am a Research Investigator in the Department of Biological Chemistry at University of Michigan. I am interested in how heterogeneity arises in bacterial populations, which has led me to study mechanisms of genome instability and mutagenesis. Mechanisms of mutagenesis have been difficult to understand because multiple factors, such as DNA replication, local sequence context, gene expression, and R-loop abundance converge to influence the mutation rate of a given genomic locus. Natural selection further confounds our understanding of mutagenic mechanisms by effectively masking from observation a subset of mutations that occur. By combining multiple disparate observations of gene expression, R-loop abundance, DNA replication, and mutagenesis, I have assembled the necessary resources to assign roles for several biological processes in mutagenesis.
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