Premature telomere shortening or telomere instability is associated with a group of rare and heterogeneous diseases collectively known as telomere biology disorders (TBDs). Here we identified two unrelated individuals with clinical manifestations of TBDs and short telomeres associated with the identical monoallelic variant c.767A>G; Y256C in RPA2. Although the replication protein A2 (RPA2) mutant did not affect ssDNA binding and G-quadruplex-unfolding properties of RPA, the mutation reduced the affinity of RPA2 with the ubiquitin ligase RFWD3 and reduced RPA ubiquitination. Using engineered knock-in cell lines, we found an accumulation of RPA at telomeres that did not trigger ATR activation but caused short and dysfunctional telomeres. Finally, both patients acquired, in a subset of blood cells, somatic genetic rescue events in either POT1 genes or TERT promoters known to counteract the accelerated telomere shortening. Collectively, our study indicates that variants in RPA2 represent a novel genetic cause of TBDs. Our results further support the fundamental role of the RPA complex in regulating telomere length and stability in humans.

中文翻译：

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杂合 RPA2 变异是端粒生物学疾病的新遗传原因


端粒过早缩短或端粒不稳定与一组罕见和异质性疾病有关，统称为端粒生物学疾病 （TBD）。在这里，我们确定了两个无关的个体，其临床表现为 TBDs 和与相同的单等位基因变异 c.767A>G 相关的短端粒;RPA2 中的 Y256C。尽管复制蛋白 A2 （RPA2） 突变体不影响 RPA 的 ssDNA 结合和 G 四链体展开特性，但该突变降低了 RPA2 与泛素连接酶 RFWD3 的亲和力，并降低了 RPA 泛素化。使用工程化敲入细胞系，我们发现 RPA 在端粒处积累，这不会触发 ATR 激活，但会导致端粒短暂且功能失调。最后，两名患者在血细胞亚群中获得了 POT1 基因或 TERT 启动子中的体细胞遗传拯救事件，这些事件已知可以抵消加速端粒缩短。总的来说，我们的研究表明，RPA2 中的变异代表了 TBD 的新遗传原因。我们的结果进一步支持 RPA 复合物在调节人类端粒长度和稳定性中的基本作用。