Agata Smogorzewska, M.D., Ph.D.
Throughout its lifetime, a cell’s DNA is under constant metabolic and environmental assault that can lead to damage. If left unchecked, the resulting genome instability can initiate cancer and a variety of other human disorders. Using Fanconi anemia and other genetic diseases as a backdrop, Smogorzewska’s research aims to elucidate the pathways that protect organ function and prevent cancer, with a focus on those that replicate and repair DNA.
Research in the Laboratory of Genome Maintenance is focused on DNA repair, with special emphasis on repair that takes place during replication. The group’s interests are broad, ranging from the molecular function of proteins involved in the DNA damage response to the cellular and in vivo consequences of deficiencies in proper DNA replication and repair.
The DNA interstrand crosslink (ICL) is the prototype DNA lesion repaired during replication. ICLs covalently link the Watson and Crick strands of the DNA, and the repair of these lethal lesions requires a dual excision of the crosslinked bases as well as 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 due to failures in the maintenance of 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.
In recent years, the lab has identified SLX4, RAD51, and UBE2T as genes mutated in Fanconi anemia patients. By identifying these and other novel genes in patients with FA and related disorders, the group is able to use insights and patient-derived tools in the quest to understand the mechanism of DNA repair at the cellular level. Currently, the prevention and treatment of tumors are the major clinical challenges for the disease. The lab is using next generation sequencing and functional analysis of identified variants to investigate the etiology and vulnerabilities of cancers in FA patients, with the goal of identifying biomarkers and treatment targets.
ICL repair deficiency is also associated with kidney and liver dysfunction. A rare human disease called karyomegalic interstitial nephritis (KIN) develops when FAN1, a nuclease that functions in ICL repair, is deficient. FAN1 has also been identified as a genetic modifier of Huntington’s disease (HD). The lab uses a mouse model of FAN1 deficiency to gain insights about the pathogenesis of KIN and HD, as well as to obtain global understanding of how genome maintenance pathways protect organ function.