The Smogorzewska laboratory studies how DNA is damaged and repaired during DNA replication. Most of our work to date explored the repair of DNA interstrand crosslinks (ICLs) that covalently link two strands of DNA and preclude proper replication and transcription. We study rare genetic diseases including Fanconi anemia and karyomegalic interstitial nephritis, which are characterized by abnormal ICL repair. Our ongoing studies aim to identify new genes, determine their role in DNA ICL repair, and illuminate the molecular pathogenesis of these diseases, including development of bone marrow failure, leukemia, squamous cell carcinoma, and kidney failure. We also develop mouse models to investigate the in vivo consequences of deficiencies in DNA repair.
Most recently, we initiated studies to understand how the replication machinery responds to what is commonly called “replication stress,” any situation that impedes normal movement of the replication fork. The goal is to understand events that unfold at the fork in order to produce daughter cells without inducing genome instability.
IDENTIFICATION OF NEW GENES NECESSARY FOR INTERSTRAND CROSSLINK (ICL) REPAIR
In the last six years, we have identified FANCP/SLX4, FANCR/RAD51, and FANCT/UBE2T. We identified FAN1 in an shRNA screen for proteins necessary for ICL repair. The Hildebrandt lab found FAN1 mutations in patients with karyomegalic interstitial nephritis and we showed that FAN1 deficiency was responsible for the cellular defects of the patients cells. Our lab continues to identify new genes involved in DNA repair.
IN VIVO CONSEQUENCES OF INAPPROPRIATE ICL REPAIR
We have made a mouse model of FAN1 deficiency and are studying the phenotypes of this mouse to gain better understanding of human disease.
MECHANISM OF ICL REPAIR
Patient cell lines are invaluable to identify mechanism of ICL repair. Especially useful are naturally occurring separation of function mutations that direct us to new functions of proteins.
UNDERSTANDING TUMORIGENESIS IN FANCONI ANEMIA
Fanconi anemia is a tumor predisposition syndrome. Patients have an increased risk (700 fold) to develop squamous cell carcinoma. The most prevalent cancer sites involve head and neck, anogenital area, esophagus, and lung. We are taking a genomic approach to understand the pathogenesis of these cancers with the hope of developing biomarkers and future treatments.