The DNA damage response (DDR) acts as a barrier to malignant transformation and is often impaired during tumorigenesis. Exploiting the impaired DDR can be a promising therapeutic strategy; however, the mechanisms of inactivation and corresponding biomarkers are incompletely understood. Starting from an unbiased screening approach, we identified the SMC5-SMC6 Complex Localization Factor 2 (SLF2) as a regulator of the DDR and biomarker for a B-cell lymphoma (BCL) patient subgroup with an adverse prognosis. SLF2-deficiency leads to loss of DDR factors including Claspin (CLSPN) and consequently impairs CHK1 activation. In line with this mechanism, genetic deletion of Slf2 drives lymphomagenesis in vivo. Tumor cells lacking SLF2 are characterized by a high level of DNA damage, which leads to alterations of the post-translational SUMOylation pathway as a safeguard. The resulting co-dependency confers synthetic lethality to a clinically applicable SUMOylation inhibitor (SUMOi), and inhibitors of the DDR pathway act highly synergistic with SUMOi. Together, our results identify SLF2 as a DDR regulator and reveal co-targeting of the DDR and SUMOylation as a promising strategy for treating aggressive lymphoma.

中文翻译：

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SLF2 的可操作缺失会驱动 B 细胞淋巴瘤发生并损害 DNA 损伤反应

DNA 损伤反应 (DDR) 作为恶性转化的屏障，在肿瘤发生过程中经常受到损害。利用受损的 DDR 可能是一种有前途的治疗策略；然而，失活机制和相应的生物标志物尚不完全清楚。从公正的筛查方法开始，我们确定了 SMC5-SMC6 复合定位因子 2 (SLF2) 作为 DDR 的调节因子和预后不良的 B 细胞淋巴瘤 (BCL) 患者亚组的生物标志物。SLF2 缺陷会导致包括 Claspin (CLSPN) 在内的 DDR 因子丢失，从而损害 CHK1 激活。根据这一机制，Slf2的基因缺失会驱动体内淋巴瘤的发生。缺乏SLF2的肿瘤细胞的特点是高水平的DNA损伤，这会导致翻译后SUMO化途径的改变作为保障。由此产生的相互依赖性赋予临床适用的 SUMO 化抑制剂 (SUMOi) 合成致死性，并且 DDR 途径的抑制剂与 SUMOi 具有高度协同作用。总之，我们的结果将 SLF2 确定为 DDR 调节剂，并揭示了 DDR 和 SUMOylation 的共同靶向作为治疗侵袭性淋巴瘤的有前途的策略。