Research

Genome instability is a critical driver in aging and age-associated pathologies such as cancer, neurodegenerative diseases, and immunodeficiency. Furthermore, many diseases defined by cancer predisposition and accelerated aging are caused by defective DNA repair proteins highlighting the importance of maintaining genome integrity. Genetic and biochemical studies have identified >150 proteins contributing to genome maintenance, yet, we still lack a complete understanding of how a complex network of proteins coordinate to achieve genome stability. Deciphering these critical molecular events remains challenging because traditional approaches cannot directly observe the dynamic assembly of large multi-protein complexes at a single DNA lesion. Using single-molecule biophysical techniques, our lab directly watches protein complexes work on DNA and observe individual biochemical reactions in real-time. Using these single-molecule methodologies combined with structural biology, biochemistry, and cell biology, our lab aims to understand how macromolecular complexes have adapted to prevent genome instability at the molecular level. 

Repair of DNA damage

It is estimated that the genomes of each human cell encounter >50,000 DNA lesions daily, and deficiencies in these DNA repair pathways lead to cancer predisposition or premature aging syndromes. Of these DNA lesions, we are particularly interested in answering critical questions regarding human DNA double-stranded break repair. DNA double-strand breaks are the most harmful DNA lesions because they disrupt both the physical and genetic continuity of the genome and, if incorrectly repaired, can lead to genome rearrangements, malignant transformation, and tumor growth. We are focused on determining how DNA repair proteins locate DNA breaks along chromatin and the critical molecular steps determining DNA repair pathway choice. Furthermore, we are interested in understanding how powerful molecular machines, such as the resectosome, are assembled and regulated at DNA breaks to promote error-free repair.

Telomere maintenance and protection

Telomere length regulation is vital for maintaining cellular homeostasis and requires a delicate balance between lengthening and shortening processes. Critically short telomeres can lead to genome instability, cellular senescence, or apoptosis, which are critical drivers in cancer development and several aging disorders, such as dyskeratosis congenita. Excessively long telomeres have also been shown to increase cancer risk. Therefore, defining how telomere length is regulated is critical for understanding cancer biology and aging. Given the complexity of telomeres, single-molecule methodologies are critical to fully understand the molecular mechanisms that govern telomere maintenance. Our lab aims to answer key mechanistic questions on these mechanisms underlying telomere length regulation in both normal and cancer cells to determine how telomeric proteins and DNA repair proteins work together to protect telomere integrity.