Chromosomal rearrangements and genome instability are both hallmarks of cancer. These rearrangements frequently arise due to activation of a highly error-prone “backup” DNA repair pathway. Microhomology-mediated end-joining (MMEJ) is largely dormant in healthy cells but allows cancer cells to adapt to chemotherapy and loss of primary DNA repair pathways. For example, MMEJ upregulation leads to poor clinical outcomes in estrogen receptor-negative breast cancer and non-small cell lung cancer (NSCLC), the deadliest cancer nationwide. Because of its importance in aggressive and treatment-resistant cancers, drugs that target MMEJ are a promising avenue for the next generation of cancer therapeuti...

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Chromosomal rearrangements and genome instability are both hallmarks of cancer. These rearrangements frequently arise due to activation of a highly error-prone “backup” DNA repair pathway. Microhomology-mediated end-joining (MMEJ) is largely dormant in healthy cells but allows cancer cells to adapt to chemotherapy and loss of primary DNA repair pathways. For example, MMEJ upregulation leads to poor clinical outcomes in estrogen receptor-negative breast cancer and non-small cell lung cancer (NSCLC), the deadliest cancer nationwide. Because of its importance in aggressive and treatment-resistant cancers, drugs that target MMEJ are a promising avenue for the next generation of cancer therapeutics. Thus, there is a critical need to understand the molecular mechanisms and functional outcomes of MMEJ. The overall goal of this proposal is to decipher the molecular mechanisms of MMEJ. MMEJ requires several DNA repair proteins, including PARP1, and the multifunctional DNA Polymerase Theta. Here, we propose an interdisciplinary approach that combines molecular biophysics and micro-/nano-engineering to directly observe the molecular mechanisms of MMEJ. We aim to answer several long-standing questions in the DNA repair and cancer biology fields, including: (1) How does PARP1 direct DNA repair towards MMEJ? (2) How do healthy cells suppress MMEJ? and (3) How does Polymerase Theta orchestrate the critical molecular steps of MMEJ? These questions are especially pressing due to the increasing clinical incidence of cancers that are resistant to PARP inhibitors (e.g., olaparib). Upregulation of MMEJ and Polymerase Theta in cancer cells underlies some of this resistance. Our mechanistic studies will be critical for understanding how cancers evade frontline chemotherapeutics. More broadly, these studies will provide a mechanistic underpinning for new drugs that target this cancer-associated DNA repair pathway.

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