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 disorders. Using Fanconi anemia and other genetic disease as a backdrop, Dr. Smogorzewska’s research aims to elucidate pathways that prevent stem cell dysfunction, and cancer development, with a focus on those that repair DNA.
The focus of the research in the Laboratory of Genome Maintenance is to understand the mechanism of DNA interstrand crosslink (ICL) repair with the overall goal to gain insights into the cellular and organismal consequences of deficiencies in this type of repair. ICL repair takes place at sites where the two strands of the DNA have become covalently linked by the byproducts of lipid peroxidation, endogenous aldehydes derived during protein and DNA demethylation, and yet unknown metabolites. The repair of these lethal lesions takes place during DNA replication and requires a dual excision of the cross-linked bases and repair of the resulting double-strand breaks. This feat is accomplished in a multi-step process mediated by the Fanconi anemia (FA) pathway and factors that promote Homologous Recombination (HR), including BRCA1 and BRCA2. FA patients lack components of this pathway and suffer from bone marrow failure and infertility presumably due to the inability to maintain hematopoietic and germline stem cells. FA is also associated with a very high incidence of cancer, most likely due to the mutagenic nature of incorrectly repaired ICLs. On the other hand, the induction of ICL is a major method of cancer treatment and often leads to excellent outcomes (e.g., cisplatin treatment of testicular cancer).
Thus, the FA pathway is of critical importance to normal development, tissue homeostasis, and in the context of cancer. Yet, many aspects of the FA pathway are still opaque. Key issues are to identify the missing players in the pathway, to understand how the FA pathway interfaces with DNA replication, and to define how the FA pathway cooperates with other forms of DNA repair to ensure genome stability. Smogorzewska’s lab approaches these questions using the power of human genetics. In the last six years, the lab has identified SLX4, RAD51, and UBE2T as genes mutated in Fanconi anemia patients. By identifying novel genes in patients with FA and related disorders, they are able to use insights and patient-derived tools in their quest to understand the mechanism of DNA repair on the cellular level.
A second branch of Dr. Smogorzewska’s research program is designed to study the organismal effects of ICL repair deficiencies. The goal is to identify the key genomic changes that lead to cancer development, to understand the mechanism of stem cell failure, and to identify the underlying cause of kidney failure when ICL repair is corrupted.