端粒是染色体末端的重复核蛋白复合物,对于维持基因组稳定性至关重要。端粒RNA,或者TERRA,是以前推测的具有异质长度的长非编码RNA,有助于封端结构和功能,并通过不依赖端粒酶的选择性延长端粒(ALT)途径促进维持端粒长度的肿瘤中的端粒重组。这里,我们研究了TERRA在宇航员辐射诱导的DNA损伤反应(DDR)中的作用,高空登山者,健康的捐献者,和细胞模型。类似于太空辐射环境中的宇航员和山的登山者。珠穆朗玛峰,体外辐射暴露促使TERRA转录增加,而模拟微重力没有。数据表明端粒双链断裂(DSB)的特定TERRADDR,并提供在端粒特异性DSB位点杂交的TERRA的直接证明,保护性TERRA的指示:端粒DNA杂交体形成。靶向端粒DSB也导致TERRA病灶在G2期的积累,支持TERRA在促进重组介导的端粒延伸中的作用。结果对涉及持续性端粒DNA损伤的情况具有重要意义,例如与慢性氧化应激相关的那些(例如,老化,全身性炎症,环境和职业辐射暴露),可以在正常人细胞中触发瞬时ALT,以及靶向TERRA作为针对ALT阳性肿瘤的治疗策略。
Telomeres are repetitive nucleoprotein complexes at chromosomal termini essential for maintaining genome stability. Telomeric RNA, or TERRA, is a previously presumed long noncoding RNA of heterogeneous lengths that contributes to end-capping structure and function, and facilitates telomeric recombination in tumors that maintain telomere length via the telomerase-independent Alternative Lengthening of Telomeres (ALT) pathway. Here, we investigated TERRA in the radiation-induced DNA damage response (DDR) across astronauts, high-altitude climbers, healthy donors, and cellular models. Similar to astronauts in the space radiation environment and climbers of Mt. Everest, in vitro radiation exposure prompted increased transcription of TERRA, while simulated microgravity did not. Data suggest a specific TERRA DDR to telomeric double-strand breaks (DSBs), and provide direct demonstration of hybridized TERRA at telomere-specific DSB sites, indicative of protective TERRA:telomeric DNA hybrid formation. Targeted telomeric DSBs also resulted in accumulation of TERRA foci in G2-phase, supportive of TERRA\'s role in facilitating recombination-mediated telomere elongation. Results have important implications for scenarios involving persistent telomeric DNA damage, such as those associated with chronic oxidative stress (e.g., aging, systemic inflammation, environmental and occupational radiation exposures), which can trigger transient ALT in normal human cells, as well as for targeting TERRA as a therapeutic strategy against ALT-positive tumors.