Bento Fabio, Longaretti Matteo, Pires Vanessa Borges, Lockhart Arianna, Luke Brian
Institute of Developmental Biology and Neurobiology (IDN), Johannes Gutenberg Universität, 55128, Mainz, Germany.
Institute of Molecular Biology (IMB), Ackermannweg 4, 55128, Mainz, Germany.
EMBO Rep. 2025 Jun;26(12):3032-3044. doi: 10.1038/s44319-025-00469-7. Epub 2025 May 22.
Telomere repeat-containing RNA (TERRA) is transcribed at telomeres and forms RNA-DNA hybrids. In budding yeast, the presence of RNA-DNA hybrids at short telomeres promotes homology-directed repair (HDR) and prevents accelerated replicative senescence. RNA-DNA hybrids at telomeres have also been demonstrated to prevent 5'end resection, an essential step for HDR. In accordance, we now demonstrate that, not only the presence, but also the removal, of RNA-DNA hybrids drives HDR at shortened telomeres during replicative senescence. Although RNase H2 is absent from short telomeres, it is quickly compensated for by the recruitment of RNase H1 and Sen1. The recruitment of RNase H1 is essential to allow for the loading of Rad51, consistent with the notion that RNA-DNA hybrids prevent Exo1-mediated end resection. In the absence of RNase H1 or Sen1 function, yeast cultures prematurely enter replicative senescence in the absence of telomerase. Furthermore, the delayed senescence phenotype observed when RNase H2 is deleted, depends on the presence of RNase H1 and Sen1. This study demonstrates the importance of transient RNA-DNA hybrids at short telomeres to regulate senescence.
端粒重复序列RNA（TERRA）在端粒处转录并形成RNA-DNA杂交体。在芽殖酵母中，短端粒处RNA-DNA杂交体的存在促进同源定向修复（HDR）并防止加速复制性衰老。端粒处的RNA-DNA杂交体也已被证明可防止5'端切除，这是HDR的关键步骤。相应地，我们现在证明，不仅RNA-DNA杂交体的存在，而且其去除，都会在复制性衰老期间驱动缩短的端粒处的HDR。尽管短端粒中不存在核糖核酸酶H2，但核糖核酸酶H1和Sen1的募集能迅速补偿其缺失。核糖核酸酶H1的募集对于允许Rad51加载至关重要，这与RNA-DNA杂交体阻止Exo1介导的末端切除的观点一致。在没有核糖核酸酶H1或Sen1功能的情况下，酵母培养物在没有端粒酶的情况下过早进入复制性衰老。此外，当核糖核酸酶H2缺失时观察到的延迟衰老表型取决于核糖核酸酶H1和Sen1的存在。这项研究证明了短端粒处瞬时RNA-DNA杂交体对调节衰老的重要性。
