In response to DNA damage from environmental and endogenous sources, cells activate an elaborate signaling network called DNA damage response (DDR). This response functions to preserve genomic integrity, which is critical for normal development and cancer prevention. The ATR kinase is a master regulator of a broad spectrum of DNA damage and replication problems.Sensors of DNA Damage, Replication and Transcription Problems: Our recent studies revealed that ATR is not only important for sensing DNA damage and replication stress, but also to problems associated with transcription. R-loop, a transcription intermediate resulting from the formation of stable RNA:DNA hybrids and a displaced single-stranded DNA (ssDNA), is a major source of genomic instability. We found that ATR is activated by R-loops and plays a critical role in suppressing R-loop-induced genomic instability, thus uncovering a new function of ATR in maintaining genome integrity. The Nguyen laboratory will continue to dissect how ATR regulates R-loop resolution in cancers. Cancer Genomics and Targeted Therapy: we found that the splicing factor mutations associated with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) induce R-loops and trigger an ATR response. Cells that express these splicing factor mutants are sensitive to ATR inhibitors, providing a new strategy to target R-loop response for the treatment of MDS and potentially other malignancies associated with RNA splicing mutations. The Nguyen laboratory will determine additional R-loop regulators in different cancer contexts to develop new therapeutic strategies in the future. The Nguyen laboratory is currently developing small molecule probes, biochemical, cell biological and genetic approaches to investigate the underlying mechanisms of sensing and resolving R-loops in different cancers. Results obtained from these researches will provide molecular insight for the development of new targeted cancer therapeutic approaches. Interested applicants should have a PhD and/or MD degree with a strong background in either biochemistry, cell biology, functional genomics, or pharmacology. The laboratory accepts Master and PhD students through Department of Pharmacology program.
