Heads of Laboratories
Laboratory of Genome Maintenance
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 to identify biomarkers or 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. The lab recently developed a mouse model of KIN that is being used to gain insights about the pathogenesis of the disease, as well as to obtain more global understanding of how genome maintenance pathways protect organ function.
B.S. in molecular biology and biochemistry, 1995
University of Southern California
The Rockefeller University
Weill Cornell Medical College
Residency in clinical pathology, 2003–2006
Massachusetts General Hospital
Harvard Medical School, 2005–2009
Assistant Professor, 2009–2015
Associate Professor, 2015–
The Rockefeller University
Burroughs Wellcome Fund Award, 2008
Irma T. Hirschl/Monique Weill-Caulier Trust Research Award, 2010
Rita Allen Foundation Scholar, 2010
Doris Duke Charitable Foundation Clinical Scientist Development Award, 2011
Pershing Square Sohn Prize, 2014
The Rockefeller University Distinguished Teaching Award, 2014
David B. Frohnmayer Early Investigator Award, 2015
Howard Hughes Medical Institute Faculty Scholar, 2016
Gabrielle H. Reem and Herbert J. Kayden Early-Career Innovation Award, 2017
Kottemann, M.C. et al. Removal of RTF2 from stalled replisomes promotes maintenance of genome integrity. Mol. Cell 69, 24–35 (2018).
Thongthip, S. et al. Fan1 deficiency results in DNA interstrand cross-link repair defects, enhanced tissue karyomegaly, and organ dysfunction. Genes Dev. 30, 645–659 (2016).
Wang, A.T. et al. A dominant mutation in human RAD51 reveals its function in DNA interstrand crosslink repair independent of homologous recombination. Mol. Cell 59, 478–490 (2015).
Wang, A.T. and Smogorzewska, A. SnapShot: Fanconi anemia and associated proteins. Cell 160, 354 (2015).
Zhou, W. et al. FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair. Nat. Genet. 44, 910–915 (2012).