澳大利亚悉尼大学Anthony J. Cesare等研究人员合作发现，同源重组在DNA损伤后促进非免疫原性的有丝分裂细胞死亡。相关论文于2025年1月13日在线发表在《自然—细胞生物学》杂志上。

研究人员通过单细胞分析和扩展的实时成像揭示了细胞周期调控的双链断裂（DSB）修复如何引导不同的细胞死亡结局。在S或G2期诱导DSB后，未解决的同源重组中间体进入有丝分裂，促使细胞在首次尝试分裂时发生非免疫原性的内源性凋亡。

相反，非同源末端连接、微同源介导的末端连接和单链退火协同作用，使受损的G1期细胞以异常分裂完成首次细胞周期，但以延迟的外源性致死性和干扰素产生为代价。靶向非同源末端连接、微同源介导的末端连接或单链退火可促进有丝分裂死亡，而抑制有丝分裂死亡则可增强干扰素的产生。

综合来看，这些数据表明，伴随累积DSB负荷的时间修复层级是预测基因组损伤后有丝分裂灾难结局的可靠指标。在这一途径中，同源重组通过促进有丝分裂致死性来抑制干扰素的产生。

据了解，DSB可引发有丝分裂灾难，这是一种复杂的抑癌现象，其特征是在细胞分裂期间或之后发生细胞死亡。

附：英文原文

Title: Homologous recombination promotes non-immunogenic mitotic cell death upon DNA damage

Author: Szmyd, Radoslaw, Casolin, Sienna, French, Lucy, Manjn, Anna G., Walter, Melanie, Cavalli, La, Nelson, Christopher B., Page, Scott G., Dhawan, Andrew, Hau, Eric, Pickett, Hilda A., Gee, Harriet E., Cesare, Anthony J.

Issue&Volume: 2025-01-13

Abstract: Double-strand breaks (DSBs) can initiate mitotic catastrophe, a complex oncosuppressive phenomenon characterized by cell death during or after cell division. Here we unveil how cell cycle-regulated DSB repair guides disparate cell death outcomes through single-cell analysis of extended live imaging. Following DSB induction in S or G2, passage of unresolved homologous recombination intermediates into mitosis promotes non-immunogenic intrinsic apoptosis in the immediate attempt at cell division. Conversely, non-homologous end joining, microhomology-mediated end joining and single-strand annealing cooperate to enable damaged G1 cells to complete the first cell cycle with an aberrant cell division at the cost of delayed extrinsic lethality and interferon production. Targeting non-homologous end joining, microhomology-mediated end joining or single-strand annealing promotes mitotic death, while suppressing mitotic death enhances interferon production. Together the data indicate that a temporal repair hierarchy, coupled with cumulative DSB load, serves as a reliable predictor of mitotic catastrophe outcomes following genome damage. In this pathway, homologous recombination suppresses interferon production by promoting mitotic lethality.

DOI: 10.1038/s41556-024-01557-x

Source: https://www.nature.com/articles/s41556-024-01557-x