阿霉素处理的癌细胞中端粒DNA在与PML核体和核纤层蛋白B1动态相互作用中的修复与错误修复

摘要(中文译文)

在上皮性肿瘤中，端粒由端粒酶维持；然而，在多柔比星（DOX）处理的MDA-MB-231乳腺癌细胞系中，我们发现在细胞生长恢复之前，端粒酶（TERT）出现了短暂抑制。细胞在晚S-G2/M期蓄积、有丝分裂滑移、八倍体化以及核纤层蛋白B1（LMNB1）减少与该反应同时发生。在11-12%的细胞中观察到端粒聚集和以端粒保护蛋白（TRF2）为标志的ALT样过程，与DNA双链断裂（γH2AX）及重组酶RAD51共定位于PML小体。这些现象由PML小体阵列预先设定，这些PML小体与减数分裂前期蛋白SPO11和DMC1的焦点近旁共定位。在第3周，细胞去多倍体化并恢复正常周期、端粒酶和丝分裂。在BRAFV600E-SK-MEL-28黑色素瘤细胞经DOX处理后也发现了ALT样小体。然而，在亚致死剂量的DOX处理后，出现了由错误修复的TRF2/γH2AX焦点侧翼排列并串联连接的PML二聚体杆状结构形成。此类PML束绕过经历MOS-微管驱动旋转的细胞核，与外周染色质相互作用并与LMNB1片段交错。此外，LMNB1大量离开核外周，形成核内流，和/或卷曲进入大的核仁周围PML小体。我们将观察结果解释为受损、衰老的癌细胞尝试利用多种机制，借助PML异构体和减数分裂蛋白进行端粒修复。

Abstract

Telomeres in epithelial tumors are maintained by telomerase; however, in the MDA-MB-231 breast cancer cell line, treated by doxorubicin (DOX), we found a transient suppression of the telomerase (TERT) before cell growth resumed. Accumulation of cells in late-S-G2/M, mitotic slippage, octaploidy, and decrease of lamin B1 (LMNB1) coincided with this response. The telomere clustering and ALT-like process marked by the telomere shelterin (TRF2) colocalised in PML bodies with DNA DSBs (γH2AX) and recombinase RAD51 were observed in 11-12% of cells. They were preset by arrays of PML-bodies juxta-colocalized with the foci of meiotic prophase proteins SPO11 and DMC1. On the 3rd week, the cells de-polyploidised and returned to the normal cycle, telomerase, and mitosis. ALT-like bodies were also found in BRAFV600E-SK-MEL-28 DOX-treated melanoma cells. However, after sublethal doses of DOX, the formation of PML dimeric rods flanked and tandemly joined by misrepaired TRF2/γH2AX foci occured. Such PML tracts, circumventing cell nuclei undergoing MOS-microtubule-driven rotation, interacted with peripheral chromatin and intermitted with LMNB1 fragments. Furthermore, LMNB1 massively left the nuclear periphery, forming intranuclear flows, and/or convoluted into large peri-nucleolar PML bodies. We interpret our observations as the attempts by damaged, senescing cancer cells to use several mechanisms exploiting PML isoforms and meiotic proteins for telomere repair.

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