2018 Mentored Investigator Grant Recipient — Chin-Chi Chen, PhD
Chin-Chi Chen, PhD
Johns Hopkins University
Determining the Role of ARID1A in 53BP1-mediated DNA Damage Repair
Project Summary
Aberrant epigenetic regulation has emerged as one of the major attributes in the pathogenesis of human cancer. Mutations of ARID1A, a core subunit of the chromatin remodeler complex, are commonly found in ovarian clear cell carcinomas (OCCC). The function of remodeler complex is crucial for multiple cell functions including transcriptional regulation, DNA methylation, and DNA damage repair. Thus, recent studies reported that loss of ARID1A increases sensitivity to DNA damaging agents and it has been attributed to defects in non-homologous end-joining (NHEJ) DNA double-strand break (DSB) repair pathway. However, little is known about how ARID1A participates in DNA damage responses (DDR). Such new knowledge is key to understanding the contribution of ARID1A in tumor suppression and to develop the precise treatment for OCCC harboring ARID1A mutations.
To elucidate the role of ARID1A in DDR, we conducted proteomic-based approaches and identified 53BP1 as a novel binding partner of ARID1A. ARID1A immunoprecipitation further validates this interaction. This finding is significant because 53BP1 has a critical role in promoting the NHEJ function and is the first time demonstrating ARID1A’s close association with a DNA damage repair factor.
Our preliminary studies demonstrate that ARID1A prevents DNA damage, mainly through the NHEJ pathway. ARID1A acts upstream of 53BP1 recruitment and is required for efficient accumulation of 53BP1 at DNA damage foci. We further characterize that the minimal ARID1A-interacting region of 53BP1, residing in the Ionizing Radiation-Induced Foci formation (IRIF) region of the 53BP1 protein.
Based on our preliminary findings, we hypothesize that ARID1A protein chaperones and directs the 53BP1 protein to DNA damage sites, where the ARID1A-containing SWI/SNF complex reorganizes the chromatin and grants access to the damage site for DDR proteins. To test this hypothesis, we will determine whether ARID1A loss hinders chromatin tethering of 53BP1 at sites of DSBs (Aim 1), investigate the mechanisms underlying the interaction of ARID1A with 53BP1 (Aim 2) and examine the phenotypes by expressing the IRIF domain of 53BP1, which competitively inhibits ARID1A and 53BP1 binding in response to DNA damage (Aim 3).
This grant is made possible by a generous donation from Phil and Judy Messing, in memory of Carol S. Messing.
Bio
Dr. Chin-Chi Chen is currently a postdoctoral researcher at the Johns Hopkins University School of Medicine in Baltimore, Maryland. Dr. Chen earned her Ph.D. in Genetics and Genomics from the University of Connecticut in 2016. She conducted her doctoral research under the mentorship of Dr. Barbara Mellone, where she focused on understanding the regulatory mechanisms of centromeric chromatin during events of cell division. As a graduate student, she was awarded the Claire M. Berg Graduate Fellowship in recognition of her research achievements. Her graduate work has resulted in several first-author publications, one of which has been highlighted in the Journal of Cell Biology. After her Ph.D., she joined a gynecologic pathology laboratory under the instructions of Dr. Ie-Ming Shih and Dr. Tian-Li Wang. Dr. Chen’s project investigates the molecular regulation of ARID1A related to the repair of DNA damage, and the pathogenic role of ARID1A mutation in ovarian cancer development. Since ARID1A mutations are highly prevalent in gynecologic cancer, her ongoing work provides a biological rationale and mechanistic insight into the development of ARID1A-based precision cancer medicine.