Chukkapalli Sahiti, Williams Keyonna, Hu Biao, Converso-Baran Kimber, Tussing Olivia, O'Brien Patrick, Neamati Nouri, Newman Erika A
Departments of Surgery, University of Michigan, Ann Arbor, MI, USA.
Frankel Cardiovascular Center Physiology and Phenotyping Core, The Rogel Cancer Center, The University of Michigan, Ann Arbor, MI, USA.
Transl Oncol. 2025 Aug;58:102433. doi: 10.1016/j.tranon.2025.102433. Epub 2025 Jun 6.
Segmental chromosomal alterations, including 11q deletion and 17q gain, are the strongest predictors of pediatric neuroblastoma relapse. These alterations result from unbalanced translocations linked to erroneous DNA repair. Breakpoint sequence analysis suggests that these abnormalities arise through a nonhomologous end-joining mechanism, indicating a potential therapeutic opportunity. While the exact components driving this DNA end-joining process in neuroblastoma remain unknown, polymerase theta-mediated end-joining (TMEJ) has been implicated in other homologous recombination-deficient cancers. Our previous work demonstrated that high-risk neuroblastoma expresses elevated levels of TMEJ components, including DNA Ligase III and Ligase I, while downregulating classical NHEJ factors (DNA Ligase IV and Artemis). Here we show that POLQ, a critical enzyme in TMEJ, is significantly upregulated in neuroblastoma. POLQ knockout impairs proliferation, enhances sensitivity to DNA damaging agents, and reduces tumor growth in vivo. These findings suggest that POLQ facilitates DNA damage tolerance in neuroblastoma and represents a viable therapeutic target.
节段性染色体改变，包括11q缺失和17q增加，是小儿神经母细胞瘤复发的最强预测指标。这些改变源于与错误DNA修复相关的不平衡易位。断点序列分析表明，这些异常是通过非同源末端连接机制产生的，这表明存在潜在的治疗机会。虽然驱动神经母细胞瘤中这种DNA末端连接过程的确切成分尚不清楚，但聚合酶θ介导的末端连接（TMEJ）已在其他同源重组缺陷型癌症中被提及。我们之前的研究表明，高危神经母细胞瘤中TMEJ成分的表达水平升高，包括DNA连接酶III和连接酶I，同时下调经典的非同源末端连接因子（DNA连接酶IV和Artemis）。在此我们表明，TMEJ中的关键酶POLQ在神经母细胞瘤中显著上调。POLQ基因敲除会损害细胞增殖，增强对DNA损伤剂的敏感性，并在体内减少肿瘤生长。这些发现表明，POLQ促进神经母细胞瘤中的DNA损伤耐受，是一个可行的治疗靶点。
