Laboratory of Genome Maintenance
Agata Smogorzewska, M.D., Ph.D.
Throughout its lifetime, a cell's DNA is under constant metabolic and environmental assault leading to damage. Left unchecked, the resulting genome instability initiates cancer and other age-related disorders. By studying rare genetic diseases, Dr. Smogorzewska's research aims to elucidate pathways that prevent cancer development, with a specific focus on those that repair DNA and those that induce permanent growth arrest in response to cellular stress.
Fanconi anemia is a recessive syndrome characterized by developmental abnormalities, bone marrow failure and cancer predisposition. Unlike healthy individuals, patients with Fanconi anemia are extremely susceptible to DNA crosslinking agents such as cisplatin and mitomycin C (MMC). Dr. Smogorzewska's research aims to understand the regulation and activity of the proteins known to be mutated in the Fanconi anemia pathway; identify factors that promote survival in Fanconi anemia cells in the setting of crosslink damage; discover and mechanistically study new components of pathways responsible for MMC resistance in human cells; and study the mechanism of senescence induction in human cells and its involvement in tumor suppression and cancer treatment responses.
Fanconi anemia patients are classified into 19 different complementation groups with each group representing a mutation in one gene. While a postdoctoral fellow, Dr. Smogorzewska discovered FANCI, one of the Fanconi anemia genes, using functional analysis of a proteomic screen that identified putative substrates of ATM and ATR, proteins that are key kinases involved in cellular responses to DNA damage. FANCI and FANCD2 are key components of the pathway and they direct the effectors of the pathway to perform repair. One of these effectors is FAN1 (a Fanconi anemia associated nuclease 1), which Dr. Smogorzewska identified in a whole genome short hairpin RNA screen in human cells which was designed to identify genes that were important for survival after DNA crosslink damage. FAN1 localizes to the sites of damage using its ubiquitin-binding domain that interacts with monoubiquitinated FANCD2. In vitro, FAN1 has nuclease activity, which is necessary for the resistance to DNA crosslink damage. The lab is now working to understand the steps at which FAN1 works during repair.
In recent work, the Smogorzewska lab studied two patients from the International Fanconi anemia registry (IFAR) — started at Rockefeller University by Arleen Auerbach in 1982 — with typical clinical features of Fanconi anemia including bone marrow failure and cancer predisposition. Mutations in SLX4 gene were identified in both patients. SLX4 is a large scaffold protein, which interacts with multiple nucleases, including XPF, MUS81 and SLX1. Together with SLX1, SLX4 forms a Holliday junction resolvase, and interactions with the other nucleases are important for DNA damage repair. Current studies focus on the mechanism of function of SLX4 and the associated proteins. Dr. Smogorzewska is also identifying other Fanconi genes using whole exome sequencing, with the ultimate goal of understanding how all of the components of the Fanconi anemia pathway ensure genome stability during DNA replication and how they suppress cancer.
Dr. Smogorzewska received her B.S. in molecular biology and biochemistry from the University of Southern California in 1995, her Ph.D. from The Rockefeller University in 2002 and her M.D. from Weill Cornell Medical College in 2003. Following a residency in clinical pathology at Massachusetts General Hospital, she joined Harvard Medical School as a postdoctoral fellow in Stephen Elledge's lab in 2005. She joined The Rockefeller University as an assistant professor in 2009. Dr. Smogorzewska is the recipient of numerous awards, including the Irma T. Hirschl Research Award and Rita Allen Foundation Scholars Program Grant in 2010, the Burroughs Wellcome Fund Career Award for Medical Scientists in 2008 and the Harold M. Weintraub Graduate Student Award in 2002.