Heads of Laboratories
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. Using Fanconi anemia as a backdrop for understanding aging and cancer, 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 uses this background to understand the cellular processes that repair DNA. In particular, her 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 15 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 that was designed to identify genes that were important for survival after DNA cross-link damage. FAN1 localizes to the sites of damage using its ubiquitin-binding domain that interacts with monoubiquitinated FANCD2. In vitro, FAN1 has a nuclease activity, which is necessary for the resistance to DNA crosslink damage. It is now clear that FAN1 also has Fanconi anemia pathway-independent functions. Germ line FAN1 mutations have been identified in karyomegalic interstitial nephritis, a chronic kidney disease; individuals with this disease lack Fanconi anemia phenotypes. The lab continues to study FAN1’s role in crosslink repair in order to understand the pathophysiology of both diseases.
Three more nucleases are implicated in crosslink repair, all of which interact with a single scaffold protein, SLX4. The Smogorzewska lab identified mutations in SLX4 in two patients from the International Fanconi Anemia Registry started at The Rockefeller University by Arleen Auerbach in 1982. These patients had typical clinical features of Fanconi anemia, including bone marrow failure and cancer predisposition. Using the cell lines from these patients, the lab showed that XPF was the essential nuclease in crosslink repair during S phase. The lab is continuing to study the genetic interactions between SLX4 and other repair pathways in the cell.
Dr. Smogorzewska is also identifying other Fanconi genes using whole exome sequencing. The ultimate goal is to understand 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 Doris Duke Charitable Foundation Clinical Scientist Development Award in 2011, 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.
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