Moreno Sara Priego, Fusté Javier Miralles, Kaiser Melanie, Li Julia Su Zhou, Nassour Joe, Haggblom Candy, Denchi Eros Lazzerini, Karlseder Jan
The Salk Institute for Biological Studies, Molecular and Cell Biology Department, 10010 N. Torrey pines Road, La Jolla, CA 92037, USA.
The Ludwig Institute for Cancer Research, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
iScience. 2023 Mar 14;26(4):106405. doi: 10.1016/j.isci.2023.106405. eCollection 2023 Apr 21.
The appropriate regulation of telomere length homeostasis is crucial for the maintenance of genome integrity. The telomere-binding protein TZAP has been suggested to regulate telomere length by promoting t-circle and c-circle excisions through telomere trimming, yet the molecular mechanisms by which TZAP functions at telomeres are not understood. Using a system based on TZAP overexpression, we show that efficient TZAP recruitment to telomeres occurs in the context of open telomeric chromatin caused by loss of ATRX/DAXX independently of H3.3 deposition. Moreover, our data indicate that TZAP binding to telomeres induces telomere dysfunction and ALT-like activity, resulting in the generation of t-circles and c-circles in a Bloom-Topoisomerase IIIα-RMI1-RMI2 (BTR)-dependent manner.
端粒长度稳态的适当调节对于维持基因组完整性至关重要。端粒结合蛋白TZAP被认为通过端粒修剪促进t环和c环切除来调节端粒长度，然而TZAP在端粒发挥功能的分子机制尚不清楚。利用基于TZAP过表达的系统，我们发现，在由ATRX/DAXX缺失导致的开放端粒染色质环境中，TZAP能有效募集到端粒，且这一过程不依赖于H3.3沉积。此外，我们的数据表明，TZAP与端粒的结合会诱导端粒功能障碍和ALT样活性，从而以布鲁姆解旋酶-拓扑异构酶IIIα-RMI1-RMI2（BTR）依赖的方式产生t环和c环。
