Research Spotlight: Dr. Jingsong Yuan

Dr. Jingsong Yuan is an Assistant Professor of Radiation Oncology in the Department of Radiation Oncology and Center for Radiological Research. Dr. Yuan's laboratory mainly focuses on deciphering the underlying molecular mechanisms that result in genomic instability and tumorigenesis, specifically, on understanding the molecular mechanisms underlying DNA replication stress response and homologous recombination (HR) DNA repair, the function of which is critical for preventing genomic instability and tumorigenesis.

1. Explore DNA damage response signaling network

Cells are continuously challenged by genotoxic agents from endogenous and exogenous sources (e.g. ionizing radiation). DNA double-strand breaks (DSBs) represent one of the most lethal forms of DNA lesions that have to be appropriately repaired for cell survival. Cells have evolutionarily conserved pathways known collectively as DNA damage response (DDR), which can sense DNA damage, propagate DNA damage signals and subsequently activate signaling cascades to evoke a multitude of cellular responses that include cell-cycle checkpoints to slow down or stall damaged cells until the resolution of DNA lesions. There are two major pathways involved in the repair of DSBs, namely non-homologous end-joining (NHEJ) pathway and homologous recombination (HR) pathway. HR is particularly important for the repair of DSBs due to its ability to accurately restore genetic information. Genomic instability and ultimately initiation of tumorigenesis could occur due to inefficient or inaccurate repair of DSBs.

In response to DSBs, phosphorylation of histone variant H2AX at serine 139 creates gH2AX, which is a key event in DDR. However, we and others showed that the MRE11-RAD50-NBS1 (MRN) complex can act independently of the H2AX-mediated DDR cascade to promote DNA end resection, which is critical for homologous recombination repair. The current working hypothesis in Yuan lab is that cells are equipped with two distinct but related DNA damage response pathways, i.e. the MRE11/RAD50/NBS1 (MRN)-dependent initial recruitment and the H2AX-dependent stable accumulation of DDR proteins to DSBs, that together complement each other and are critical for DNA damage repair and cell survival (see Figure).


2. Investigation of novel HR repair factors involved in breast cancer development.

The two major breast cancer susceptibility genes, BRCA1 and BRCA2, work in concert in the common HR pathway to protect the genome during DNA replication. Emerging evidence indicates that HR repair is disrupted by numerous mechanisms in sporadic breast cancers, and therefore a significant fraction of sporadic breast cancers present a BRCAness or BRCA-like profile (defects in HR repair pathways), but do not have mutations in BRCA1, BRCA2 or other known genes involved in HR repair.

One of the studies in the Yuan lab is to identify novel HR repair factors and explore HR defects in sporadic breast cancers. The RAD51 recombinase plays a central role in HR. Dr. Jingsong Yuan identified a new RAD51-binding protein FIGNL1 (fidgetin-like 1). FIGNL1 specifically interacts with RAD51 via its conserved RAD51-binding domain. Cells depleted of FIGNL1 show defective HR repair. Interestingly, FIGNL1 is recruited to sites of DNA damage in a manner that is independent of BRCA2, RAD51, and likely, RAD51 paralogs. Conversely, FIGNL1 depletion does not affect the loading of RAD51 onto single-strand DNA. Excitingly, bioinformatics analysis of whole-exome sequencing data of cancer samples identified considerable mutations, including nonsense mutations, in genes coding FIGNL1 complex. Further study in Yuan lab will elucidate the molecular mechanisms of FIGNL1 protein complex in HR repair, examine the molecular defects of FIGNL1 mutations and explore whether deficiency in FIGNL1 protein complex would lead to BRCA-like profile in sporadic breast cancer.

In summary

The Yuan lab uses a variety of techniques, including tandem affinity purification for studying protein-protein interactions and CRISPR/cas9 mediated genome editing in mammalian cells (gene knock-out, knock-in, genomic deletion and translocation). Yuan lab has ample experience in deciphering the mechanisms of DNA replication stress response and DNA repair. Yuan lab envisions leveraging its expertise in DNA damage repair and translating into the realm of cancer biology and therapeutics. Studies in Yuan lab will lead to a better understanding of how and why DDR impacts on myriad cellular functions, how such complex programs are orchestrated, and ultimately how to harness our knowledge on DDR for treating diseases including cancer.