Damage to the genetic material of our cells can have many undesired consequences. It may lead to cell death, growth arrest, inappropriate growth or mutations. The outcomes of these on the organismal levels are failure of essential organ function or cancer. Rare human genetic diseases have enlightened us about how lack of DNA repair and thus persistence of DNA damage in our cells leads to these problems. Our laboratory studies two DNA repair diseases, Fanconi anemia (FA) and Karyomegalic Interstitial Nephritis (KIN). Patients with FA have developmental abnormalities including skeletal anomalies and bone marrow failure, which leaves them unable to produce enough red blood cells to carry oxygen, platelets to prevent bleeding or white blood cells to fight off infections. FA patients als have a very high predisposition to developing cancer including acute myelogenous anemia that occurs paradoxically in the setting of the bone marrow failure, head and neck cancers, and gynecologic cancers. KIN patients develop kidney failure and need dialysis and kidney transplantation. Although rare, these diseases can be used as powerful models for understanding how bone marrow and kidneys fail, and how cancer develops when the DNA is not repaired. We strive to understand the molecular underpinnings of these diseases, connections and differences between them. Even though the patients with the two diseases show different health problems, the cells from the patients lack the ability to repair a very particular type of DNA damage, interstrand crosslink, which links the two strands of DNA together precluding their separation. This kind of damage may be caused by environmental toxins, metabolites from cellular processes or by chemotherapy during cancer treatment. In this grant, we propose to concentrate our attention on the nucleases involved in processing of the interstrand crosslinks. We have identified SLX4 mutations in three patients with Fanconi anemia in the International Fanconi anemia registry. With our collaborators, we have described FAN1 mutations in KIN patients. In the first two aims we propose to use the patient cell lines to understand the pathogenesis of the two diseases. Using molecular approaches we want to understand the interaction of SLX4- bound nucleases as well as FAN1, their different requirements across cell cycle and across different DNA lesions and how they genetically interact with other DNA repair pathways in the cell. In the third aim, we will take a biochemical approach to understand these nucleases. Performing in vitro experiments, we want to study how they work on damaged DNA. Our goal is to have a detailed picture of how the cell deals with crosslinks in hopes of manipulating the repair pathways for therapeutic applications.

Public Health Relevance

Failure to repair damage that occurs daily in DNA, the genetic material of our cells, contributes to many age- related disorders including cancer and chronic kidney disease. Chronic kidney disease affects 20 million people and there are over a million and a half cancers diagnosed yearly in the United States alone. We use patient cell lines with genetic deficiencies in DNA repair to gain detailed knowledge of how cells repair the DNA damage in hopes of understanding these conditions and facilitating developments of new treatments.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Molecular Genetics B Study Section (MGB)
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Qasba, Pankaj
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Rockefeller University
Other Domestic Higher Education
New York
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Asur, Rajalakshmi S; Kimble, Danielle C; Lach, Francis P et al. (2018) Somatic mosaicism of an intragenic FANCB duplication in both fibroblast and peripheral blood cells observed in a Fanconi anemia patient leads to milder phenotype. Mol Genet Genomic Med 6:77-91
Kimble, Danielle C; Lach, Francis P; Gregg, Siobhan Q et al. (2018) A comprehensive approach to identification of pathogenic FANCA variants in Fanconi anemia patients and their families. Hum Mutat 39:237-254
Lv, Zongyang; Rickman, Kimberly A; Yuan, Lingmin et al. (2017) S. pombe Uba1-Ubc15 Structure Reveals a Novel Regulatory Mechanism of Ubiquitin E2 Activity. Mol Cell 65:699-714.e6
Cottineau, Julien; Kottemann, Molly C; Lach, Francis P et al. (2017) Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency. J Clin Invest 127:1991-2006
Donovan, Frank X; Kimble, Danielle C; Kim, Yonghwan et al. (2016) Paternal or Maternal Uniparental Disomy of Chromosome 16 Resulting in Homozygosity of a Mutant Allele Causes Fanconi Anemia. Hum Mutat 37:465-8
Thongthip, Supawat; Bellani, Marina; Gregg, Siobhan Q et al. (2016) Fan1 deficiency results in DNA interstrand cross-link repair defects, enhanced tissue karyomegaly, and organ dysfunction. Genes Dev 30:645-59
Kutler, David I; Patel, Krupa R; Auerbach, Arleen D et al. (2016) Natural history and management of Fanconi anemia patients with head and neck cancer: A 10-year follow-up. Laryngoscope 126:870-9
Wang, Anderson T; Kim, Taeho; Wagner, John E et al. (2015) A Dominant Mutation in Human RAD51 Reveals Its Function in DNA Interstrand Crosslink Repair Independent of Homologous Recombination. Mol Cell 59:478-90
Ouyang, Jian; Garner, Elizabeth; Hallet, Alexander et al. (2015) Noncovalent interactions with SUMO and ubiquitin orchestrate distinct functions of the SLX4 complex in genome maintenance. Mol Cell 57:108-22
Rickman, Kimberly A; Lach, Francis P; Abhyankar, Avinash et al. (2015) Deficiency of UBE2T, the E2 Ubiquitin Ligase Necessary for FANCD2 and FANCI Ubiquitination, Causes FA-T Subtype of Fanconi Anemia. Cell Rep 12:35-41

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