PKL1-associated ASF1A phosphorylation in radiation therapy response (Radiation Medicine and Markey Cancer Center Collaborative Bench to Bedside pilot)

Radiation therapy (RT) stands as a pivotal treatment approach for nearly half of cancer patients and contributes to the management of 40% of those successfully cured. Nevertheless, certain tumor types display innate resistance to radiotherapy, while others relapse shortly after treatment due to acquired resistance. Enhancing the efficacy of radiotherapy remains a critical goal. Polo-like kinase 1 (PLK1), a cell cycle regulator prevalent in cancer cells, has exhibited promise in cancer treatment. Existing evidence and our prior research have implicated PLK1 in the regulation of DNA damage response (DDR), although the underlying mechanism requires further elucidation. Anti-silencing function 1A (ASF1A) is recognized for its role as a histone chaperone, participating in DNA damage repair. This proposal centers on our core hypothesis: PLK1 phosphorylation of ASF1A at S166 triggers its degradation, impairing DNA repair mechanisms and sensitizing cancer cells to RT. This hypothesis is supported by our preliminary findings: (1) PLK1 interacts with and phosphorylates ASF1A at S166, (2) PLK1 phosphorylation influences ASF1A stability, and (3) PLK1-associated ASF1A phosphorylation modulates cellular sensitivity to DNA damage-inducing agents. Our investigation is structured around two distinct aims: Aim 1. Dissect the regulatory mechanism of PLK1 phosphorylation on ASF1A and its functional consequences. Aim 2: Investigate the impact of PLK1-associated ASF1A phosphorylation on RT response. The fruition of our efforts will yield a comprehensive understanding of PLK1's role in repressing the DDR pathway and inducing chromosomal instability. This insight holds the potential to open new avenues for therapeutic interventions aimed at augmenting the effectiveness of radiotherapy and analogous treatments designed to provoke DNA damage in cancer therapy.