Genomic integrity maintenance is a fundamental function to sustain life because DNA alterations such as mutations, chromosomal rearrangements, and deletions are causative factors of disease, tumorigenesis, and cell death. Cells encounter a large number of DNA lesions daily, jeopardizing the integrity of the genome, with DNA double-strand breaks (DSBs) being the most significant. The deleterious nature of DSBs is underscored by the fact that a single unrepaired DSB can cause cell death and misrepaired DSBs can result in chromosomal aberrations such as translocations and large-scale deletions. Chromosomal aberrations can result in genomic instability, a hallmark of cancer development. The cellular response to DSBs is extensive and includes recognition of the DNA lesion, signal transduction responses including modulation of the cell cycle, and, finally, repair of the DSB.
The goal of the Davis Lab is to uncover the mechanisms that modulate the cellular response to DSBs. We are motivated by the fact that a more complete understanding of these mechanisms will provide insight into how cells protect their genome and how dysregulation of these mechanisms can drive cancer etiology and how they could potentially be exploited to lead to the development of more effective cancer therapies.
The cellular response to DSBs is extensive and includes recognition of the DNA lesion, signal transduction responses including modulation of the cell cycle, and, finally, repair of the DSB. The goal of the Davis lab is to uncover the mechanisms that modulate the cellular response to DSBs, with a focus on how the DNA-dependent protein kinase (DNA-PK) regulates these processes.
DNA-PK plays an essential role in the repair of DNA double-stranded breaks (DSBs) mediated by the non-homologous end-joining (NHEJ) pathway. DNA-PK is a holoenzyme consisting of a DNA-binding (Ku70/Ku80) and catalytic (DNA-PKcs) subunit. DNA-PKcs is a serine/threonine protein kinase that is recruited to DSBs via Ku70/80 and is activated once the kinase is bound to the DSB ends. Our research aims to uncover the role of DNA-PK in the recognition of DNA lesions, propagating signal transduction pathways, modulating various DNA repair pathways, and influencing DSB repair pathway choice. We use a combination of biochemistry, cell biology, microscopy, proteomics, and novel mouse models to understand how DNA-PK and post-translational modifications of DNA-PK regulate these processes.
There is a delicate and synchronized balance that allows a cell to select the appropriate DNA repair pathway for each DNA lesion that it encounters. This balance is pivotal because erroneous or dysregulated DNA repair can result in mutations and chromosomal aberrations, which are known to drive genomic instability. Cancers driven by defects in DNA repair pathways were once thought to be limited to rare inherited mutations in a few DNA repair proteins, but data generated by the Cancer Genome Atlas shows that the vast majority of cancers are genomically unstable and thus likely have acquired a DNA repair defect.
Our research aims to identify novel mutations in DNA repair proteins in breast, pancreatic, and head and neck cancers that drive aberrant DNA repair and signaling, resulting in carcinogenesis. The goal is to clearly define how these mutations affect specific DNA repair pathways to identify agents or combined modality therapies with radiation treatment that selectively kill cancers with these mutations. Furthermore, cancers with a loss in a DNA repair component typically become addicted to another repair pathway(s) to survive and proliferate. This addiction can be exploited therapeutically by inhibiting the DNA repair pathway to the cancer cell has become addicted. We use a combination of genomics, proteomics, biochemistry, cell biology, microscopy, and tumorigenic mouse models to understand how aberrant DSB repair and signaling results in tumorigenesis and how these defects can be exploited therapeutically.
A main component of the cellular response to DNA damage is a signaling cascade that is driven primarily by phosphorylation events on serine/threonine residues. A significant body of work has identified and characterized the protein kinases and their substrates in this process, but the role of protein phosphatases in the DNA damage response is still in the preliminary stages. Our goal is to identify the phosphatases and the mechanisms regulating these enzymes in the cellular response to DNA damage, with a keen interest in the protein phosphatase 2A (PP2A). We use a combination of biochemistry, cell biology, microscopy, and proteomics to understand how protein phosphatase modulates the DNA damage response.