Research Projects
Research Projects
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Repair of DNA damage is crucial to prevent accumulation of mutations that can cause human disease, such as cancer. Our lab studies how double-strand breaks in the DNA, one of the most lethal types of DNA lesions, are repaired. Many proteins are important for DNA repair including the Shu complex and the Rad51 paralogs, whose mutation is associated with breast and ovarian cancer and Fanconi anemia.
Our lab uses cell biological, molecular, and genetic approaches to study the role of double-strand break repair proteins, such as the Shu complex and the Rad51 paralogs, in response to DNA damage. By understanding the mechanism of double-strand break repair and the role of DNA repair proteins in this process, we will uncover mechanisms of tumorigenesis and cancer progression. We will then use this knowledge to aid in diagnosis/prognosis of different types of cancers and to find novel therapeutic targets.
Reclassification of RAD51 paralog variants of unknown significance in breast and ovarian cancers
Reclassification of RAD51 paralog variants of unknown significance in breast and ovarian cancers
Many breast and ovarian cancer patients have mutations in the RAD51 paralogs. We aim to identify which of these mutations are cancer-causing and develop personalized treatment strategies for these patients.
The RAD51 paralogs work together as essential players in the homologous recombination DNA repair pathway to repair DNA double-strand breaks. Misrepair of DNA double-strand breaks can lead to mutations and chromosomal rearrangements, hallmarks of cancer. Notably, several mutations which alter the DNA repair functions of the RAD51 paralogs have strong ties to hereditary breast and ovarian cancers and these genes are now on cancer genetic screening panels. Of the RAD51 paralogs, hundreds of missense mutations have been identified in RAD51C and RAD51D, the majority of which are clinically classified as variants of unknown functional significance.
As part of the ongoing work, we are performing a comprehensive screen of these cancer-identified variants to characterize each mutation’s impact on the molecular roles of the RAD51 paralogs, RAD51C and RAD51D, in homologous recombination and DNA replication. By determining how an individual cancer variant impacts cellular function, we will be able to determine how cancer developed and help inform the clinical management of breast and ovarian cancer patients harboring these mutations.
Investigating the connections between DNA repair gene mutations and environmental toxicants
Investigating the connections between DNA repair gene mutations and environmental toxicants
A central theme in our lab is understanding how mutations in our genes are influenced by environmental exposures. This research project investigates how mutations in DNA repair genes, such as the RAD51 paralogs, affect cells' ability to handle DNA damage from alkyating chemicals.
Alkylating chemicals are commonly found in our environment and even used for some cancer treatments. Using state-of-the-art cellular and molecular techniques, such as single molecule replication fork analysis, we will uncover how different patient mutations impact DNA repair function and how these defects might increase cancer risk, particularly when individuals are exposed to environmental genotoxins and mutagens. These findings will enable physicians and researchers evaluate cancer risk in patients with RAD51 paralog mutations and improve our understanding of how multiple DNA repair pathways work together to maintain genome stability.
Targeting alternative DNA repair pathways in homologous recombination deficient cancer cells
Targeting alternative DNA repair pathways in homologous recombination deficient cancer cells
This image shows single DNA molecules that are undergoing replication by labeling the DNA with fluorescent analogs such as IdU and CldU. In cells mutant for RAD51 paralogs, DNA continues to replicate even when damaged, suggesting that alternative pathways are responsible for the repair of DNA double-strand breaks.
Cancer cells with mutations in the RAD51 paralogs cannot repair double-stranded DNA breaks using homologous recombination repair, and must be using alternative pathways to repair harmful damage. We aim to identify these alternative repair pathways and develop therpaies to target them in cancer cells.
DNA damage can block DNA replication fork progression and lead to fork collapse. To avoid cell death, cancer cells have developed mechanisms to bypass DNA damage to ensure the continuation of DNA replication. One of these pathways is a template-switching mechanism, in which the replicating DNA utilizes the newly replicating DNA on the opposite strand as a DNA repair template. This pathway employs RAD51 paralogs to guide the formation of RAD51 nucleoprotein filaments which find the homologous DNA. In RAD51 paralog-deficient cancer cells, the cells must utilize alternative DNA damage tolerance mechanisms to bypass the DNA damage. Using genomewide screens, we have identified alternative pathways that become essential upon RAD51 paralog loss. By therapeutically targeting this pathways, we aim to uncover new treatment strategies for homologous recombination deficient tumors and molecularly determine their contribution to DNA replication dynamics and chemotherapy resistance.
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