The lab has had a long-standing interest in chromatin modifications – those that occur on histones as well as on DNA. While these modifications have been well-studied in relation to transcriptional regulation, their relationship to genome integrity has been less clear. We previously established roles for both histone and DNA demethylases in DNA repair and genomic stability (Dango & Mosammaparast et al., Mol Cell, 2011; Mosammaparast et al., J Cell Biol, 2013). This led us to the discovery of a ubiquitin-dependent mechanism that recruits a demethylase-helicase complex to specific regions in the cell nucleus, defining the first known pathway by which cells specifically sense aberrant base modifications on nucleic acids (Brickner et al., Nature, 2017)

We now have several lines of investigation related to this pathway:

What is the mechanistic basis for this signaling pathway, and what is the sensor? We have significant evidence that aberrant RNA methylation marks on nascent pre-mRNAs activate this pathway, and that this damage is sensed within the context of the spliceosome (Tsao et al., Mol Cell, 2021; see figure below). We are actively investigating other factors that may regulate this signaling pathway.

Can this pathway be targeted for cancer therapy? In collaboration with Nicolas Reynoird (CNRS, France) and Pawel Mazur (MD Anderson), we have found a set of post-translational modifications on a ubiquitin ligase that can be targeted by small molecule inhibitors. Strikingly, these improve responses to commonly used chemotherapies for certain cancers (Lukinovic et al., under revision).

There are clear connections between this pathway and other nucleic acid metabolism pathways, in particular RNA processing (Soll et al., JBC, 2018). We are trying to understand the function of this pathway in physiological RNA processing and how this may be connected to other signaling mechanisms, such as innate immune pathways.

We have broadened our studies on ubiquitin-dependent signaling to include other pathways relevant for stress responses, such as inflammatory signaling (Zhao et al., Mol Cell, 2018). In addition, our group has had a long-standing collaboration with Alessandro Vindigni, whose group studies DNA replication dynamics during DNA damage. This is particularly important because replication fork progression and fork protection play key roles in chemotherapy responses, particularly in the context of BRCA1/2 deficient tumors (Lemacon et al., Nature Commun, 2017; Byrum et al., J Cell Biol, 2019, Carvajal-Maldonado D et al., Nucleic Acids Res, 2019, Byrum et al., Trends Cell Biol., 2019).

highly sensitive quantitative approaches to analyze DNA repair rates in vivo. To this end, we have developed rapid, quantitative tandem mass spectrometry (MS/MS) approaches to analyze base lesions in cells as well as in vitro (Rodell et al., Methods Mol Biol., 2022).We have also adapted such methods to quantify RNA modifications, which we have found play a role in alkylation damage signaling (Tsao et al., Mol Cell, 2021; Tsao et al., STAR Methods, 2022). Finally, we have begun to apply the same technology to measure replication rates in diverse biological systems (Ashour et al., in preparation).