The Dang 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.
Genomic instability, a hallmark of many cancers, arises from a variety of cellular processes in the genome including DNA replication and transcription. 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.
R-loop is a transcription intermediate resulting from the formation of stable RNA:DNA hybrids and a displaced single-stranded DNA (ssDNA). R-loops are a major source of replication stress and their dysregulations are associated with different human diseases such as neurological disorders and cancers.
Sensors of DNA damage, Replication and Transcription Problems
Our recent studies revealed that single-stranded DNA binding protein (RPA) is a sensor of R-loops and regulates the function of RNaseH1, an enzyme that removes the RNA moiety in RNA:DNA hybrids. RPA-coated ssDNA (RPA-ssDNA) is a key structure in DNA replication stress and DNA damage to recruit different factors important for maintaining genome stability.
In addition, we found that ATR is activated by R-loops and plays a critical role in suppressing R-loop-induced genomic instability.
Altogether, our studies revealed that ATR is not only important for sensing DNA damage and replication stress, but also to problems associated with transcription.
We will combine state-of-the-art molecular biology and biochemistry with cell imaging technology to dissect additional regulators of R-loops.
Cancer Genomics and Targeted Therapy
We recently found that 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.
Based on our pre-clinical evidence, a phase Ib clinical trial is currently testing the safety and efficacy of ATR inhibitor, AZD6738 for patients with progressive MDS or CMML (NCT03770429).
Our laboratory will continue to determine additional R-loop regulators in different cancer contexts to develop new therapeutic strategies.
