Turner Joshua L, Moore Georgia, McCraw Tyler J, Mason Jennifer M
Department of Genetics and Biochemistry, Clemson University.
bioRxiv. 2025 Feb 8:2025.02.07.637121. doi: 10.1101/2025.02.07.637121.
Homologous recombination maintains genome stability by repairing double strand breaks and protecting replication fork stability. Defects in homologous recombination results in cancer predisposition but can be exploited due to increased sensitivity to certain chemotherapeutics such as PARP inhibitors. The NEK8 kinase has roles in the replication response and homologous recombination. NEK8 is overexpressed in breast cancer, but the impact of NEK8 overexpression on homologous recombination has not been determined. Here, we demonstrate NEK8 overexpression inhibits RAD51 focus formation resulting in a defect in homologous recombination and degradation of stalled replication forks. Importantly, NEK8 overexpression sensitizes cells to the PARP inhibitor, Olaparib. Together, our results suggest NEK8 overexpressing tumors may be recombination-deficient and respond to chemotherapeutics that target defects in recombination such as Olaparib.
同源重组通过修复双链断裂和保护复制叉稳定性来维持基因组稳定性。同源重组缺陷会导致癌症易感性，但由于对某些化疗药物（如PARP抑制剂）的敏感性增加，这种缺陷可被利用。NEK8激酶在复制反应和同源重组中发挥作用。NEK8在乳腺癌中过表达，但NEK8过表达对同源重组的影响尚未确定。在这里，我们证明NEK8过表达会抑制RAD51焦点形成，导致同源重组缺陷和停滞复制叉的降解。重要的是，NEK8过表达使细胞对PARP抑制剂奥拉帕尼敏感。总之，我们的结果表明，NEK8过表达的肿瘤可能存在重组缺陷，并对靶向重组缺陷的化疗药物（如奥拉帕尼）有反应。
