Telomeres are a significant challenge to DNA replication and are prone to replication stress and telomere fragility. The shelterin component TRF1 facilitates telomere replication but the molecular mechanism remains uncertain. By interrogating the proteomic composition of telomeres, we show that mouse telomeres lacking TRF1 undergo protein composition reorganisation associated with the recruitment of DNA damage response and chromatin remodellers. Surprisingly, mTRF1 suppresses the accumulation of promyelocytic leukemia (PML) protein, BRCA1 and the SMC5/6 complex at telomeres, which is associated with increased Homologous Recombination (HR) and TERRA transcription. We uncovered a previously unappreciated role for mTRF1 in the suppression of telomere recombination, dependent on SMC5 and also POLD3 dependent Break Induced Replication at telomeres. We propose that TRF1 facilitates S-phase telomeric DNA synthesis to prevent illegitimate mitotic DNA recombination and chromatin rearrangement.

中文翻译：

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TRF1避免了在小鼠端粒上的染色质重塑，重组和复制依赖性断裂诱导复制

端粒是DNA复制的重大挑战，容易产生复制压力和端粒脆性。防护蛋白成分TRF1促进端粒复制，但分子机制仍不确定。通过询问端粒的蛋白质组学组成，我们表明缺乏TRF1的小鼠端粒经历与DNA损伤反应和染色质重塑剂募集相关的蛋白质组成重组。出人意料的是，mTRF1抑制端粒处早幼粒细胞白血病（PML）蛋白，BRCA1和SMC5 / 6复合物的积累，这与同源重组（HR）和TERRA转录增加有关。我们发现了mTRF1在抑制端粒重组中的作用，该作用先前尚未得到认识，它依赖于SMC5以及依赖POLD3的端粒断裂诱导复制。