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Kristina H. Schmidt

Professor

CONTACT

Office: ISA 6210
Phone: (813) 974-1592
Lab: ISA 6058
Email

EDUCATION

• Diploma (B.S./M.S.) in Biology, University of Leipzig (Germany)
• Ph.D. in Molecular Biology, University of Edinburgh (UK)
• Postdoctoral Fellow, University of California - San Diego

RESEARCH

Bloom Syndrome (BSyn); BLM helicase; Chromosome Breakage; DNA Replication, Recombination, Repair; Repair of Spontaneous and Induced DNA Damage

Current Research

In the Schmidt lab, our primary goal is to better understand the fundamental mechanisms by which eukaryotic cells preserve the integrity of their genome. Studies in the yeast Saccharomyces cerevisiae and in human cells have implicated numerous genes in the maintenance of genome stability, including those that function in DNA recombination, repair, and replication, as well as in the DNA damage response, oxidative defense, and telomere maintenance.

Cells with defects in these pathways can accumulate mutations, both small (point mutations, microsatellite expansion/deletions) and large (chromosomal rearrangements, e.g., translocations, chromosome fusions, inversions, deletions and duplications), all of which can be deleterious to the cell by interfering with cell proliferation and gene expression.

The Cellular and Molecular Functions of Human Bloom Syndrome Helicase BLM

Our research investigates the cellular and molecular roles of the human BLM protein, a DNA helicase that is particularly effective at unwinding secondary structures in DNA that are G-rich, such as G-quadruplexes, and plays significant roles in the repair of DNA double-strand breaks.

Mutations in the BLM gene are associated with Bloom syndrome (BSyn), an autosomal recessive disorder that is characterized by an extraordinary predisposition to cancer at a young age, and short stature. Other clinical features may include sun-sensitive skin, immunodeficiency, subfertility, microcephaly, and an increased risk of developing type-2 diabetes early in life. Cells from persons with BSyn show elevated levels of sister-chromatid exchanges, chromatid breaks, quadriradial chromosomes, micronuclei, and ultrafine bridges in mitosis.

Our research aims to elucidate how BLM prevents such chromosome aberrations and suppresses cancer. We focus on understanding the function and regulation of physical interactions between the BLM helicase and DNA maintenance and repair factors that act with BLM at its various substrates throughout the human genome. In addition to physical interactions, we also investigate genetic interactions of BLM to better understand how cells respond to the absence of the BLM helicase.

Additional efforts in the lab are aimed at determining the functional impact of non-synonymous, single-nucleotide polymorphisms in the BLM gene, and at elucidating the structure and function of the >600-amino-acid intrinsically disordered tail that extends from the helicase core of the BLM protein. 

 Utilizing S. cerevisiae to Study Genome Instability

The Schmidt lab also utilizes the budding yeast Saccharomyces cerevisiae as a model system to identify genes involved in maintaining genome stability and characterize their interaction with various DNA metabolic pathways. Our work particularly focuses on factors that function at the interface between DNA replication and repair, such as the Sgs1 helicase, which is the yeast homolog of human BLM, and the Rrm3 helicase, a yeast homolog of human Pif1.

Our current work utilizes a wide range of genetic, cellular, and biochemical techniques to investigate how Sgs1 and Rrm3 contribute to replication fork progression, prevent the initiation of aberrant recombination events, and suppress chromosomal instability.

SELECTED PUBLICATIONS

Gupta SV, Campos L, Schmidt KH. Mitochondrial superoxide dismutase Sod2 suppresses nuclear genome instability during oxidative stress. Genetics. (2023) Aug 28:iyad147.

Muellner J and Schmidt KH (2023) Helicase activities of Rad5 and Rrm3 genetically interact in the prevention of recombinogenic DNA lesions in Saccharomyces cerevisiae. DNA Repair; 126:103488.

Shastri VM, Subramanian V and Schmidt KH. (2021) A novel cell-cycle-regulated interaction of the Bloom syndrome helicase BLM with Mcm6 controls replication-linked processes. Nucleic Acids Res. 49(15):8699-8713

Subramanian V, Rodemoyer B, Desler C, Rasmussen LJ and Schmidt KH (2021) Bloom syndrome DNA helicase deficiency causes oxidative stress and mitochondrial network changes. Sci. Rep. 11(1):2157.

Doerfler L, Syed S, and Schmidt KH (2018) Sgs1 Binding to Rad51 Stimulates Homology-Directed DNA Repair in Saccharomyces cerevisiae. Genetics 208(1):125-138.

Salahuddin Syed, Claus Desler, Lene J. Rasmussen, Kristina H. Schmidt (2016) A Novel Rrm3 Function in Restricting DNA Replication via an Orc5-Binding Domain Is Genetically Separable from Rrm3 Function as an ATPase/Helicase in Facilitating Fork Progression. PLoS Genet. Dec 6;12(12):e1006451.

Vivek M. Shastri, Kristina H Schmidt: Cellular defects caused by hypomorphic variants of the Bloom syndrome helicase gene BLM. Mol Genet Genomic Med. 2016 Jan;4(1):106-19.

Jessica A Kennedy, Salahuddin Syed, Kristina H Schmidt: Structural Motifs Critical for In Vivo Function and Stability of the RecQ-Mediated Genome Instability Protein Rmi1. PLoS ONE 2015;10(12):e0145466.

Lillian Doerfler, Kristina H. Schmidt: Exo1 phosphorylation status controls the hydroxyurea sensitivity of cells lacking the Pol32 subunit of DNA polymerases delta and zeta. DNA Repair (Amst). 2014 Dec;24:26-36.

Jessica A Kennedy, Gary W Daughdrill, Kristina H Schmidt: A transient -helical molecular recognition element in the disordered N-terminus of the Sgs1 helicase is critical for chromosome stability and binding of Top3/Rmi1. Nucleic Acids Res. 2013 Dec;41(22):10215-27.

Hamed Mirzaei, and Kristina H Schmidt: Non-Bloom syndrome-associated partial and total loss-of-function variants of BLM helicase. Proc Natl Acad Sci U S A. 2012 Nov 20;109(47):19357-62.

GRADUATE STUDENTS

• Sonia Vidushi Gupta
• Julius Muellner
• Brian Rodemoyer
• Vivek Shastri
• Vivek Somasundaram
• Veena Subramanian