Department of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA.
Cell Rep. 2020 Nov 10;33(6):108379. doi: 10.1016/j.celrep.2020.108379.
The telomeric shelterin protein telomeric repeat-binding factor 2 (TRF2) recruits origin recognition complex (ORC) proteins, the foundational building blocks of DNA replication origins, to telomeres. We seek to determine whether TRF2-recruited ORC proteins give rise to functional origins in telomere repeat tracts. We find that reduction of telomeric recruitment of ORC2 by expression of an ORC interaction-defective TRF2 mutant significantly reduces telomeric initiation events in human cells. This reduction in initiation events is accompanied by telomere repeat loss, telomere aberrations and dysfunction. We demonstrate that telomeric origins are activated by induced replication stress to provide a key rescue mechanism for completing compromised telomere replication. Importantly, our studies also indicate that the chromatin remodeler SNF2H promotes telomeric initiation events by providing access for ORC2. Collectively, our findings reveal that active recruitment of ORC by TRF2 leads to formation of functional origins, providing an important mechanism for avoiding telomere dysfunction and rescuing challenged telomere replication.
端粒遮蔽蛋白端粒重复结合因子 2（TRF2）招募起始识别复合物（ORC）蛋白，ORC 蛋白是 DNA 复制起始点的基本组成部分，到端粒。我们试图确定 TRF2 招募的 ORC 蛋白是否在端粒重复序列中产生功能性起始点。我们发现，通过表达 ORC 相互作用缺陷的 TRF2 突变体来减少端粒募集的 ORC2，会显著减少人类细胞中端粒起始事件。这种起始事件的减少伴随着端粒重复序列的丢失、端粒异常和功能障碍。我们证明，端粒起始点通过诱导复制应激被激活，为完成受损的端粒复制提供了关键的挽救机制。重要的是，我们的研究还表明，染色质重塑因子 SNF2H 通过为 ORC2 提供进入途径来促进端粒起始事件。总的来说，我们的发现表明，TRF2 对 ORC 的主动招募导致功能性起始点的形成，为避免端粒功能障碍和挽救有挑战的端粒复制提供了重要机制。
