UMR7258 Centre National de la Recherche Scientifique (CNRS), UMR1068 Institut National de la Santé et de la Recherche Médicale (INSERM), UM105 Aix Marseille University, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), Laboratoire Labellisée par la Ligue Nationale Contre le Cancer, F-13009 Marseille, France.
U1152 INSERM, Department of Genetics, Assistance Publique-Hôpitaux de Paris, Bichat Hospital, Paris Cité University, F-75018 Paris, France.
Genes Dev. 2024 Sep 19;38(15-16):755-771. doi: 10.1101/gad.352032.124.
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 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 genes or promoters known to counteract the accelerated telomere shortening. Collectively, our study indicates that variants in 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.
端粒缩短或不稳定与一组罕见且异质性的疾病有关，统称为端粒生物学疾病（TBDs）。在这里，我们鉴定了两个无关联的个体，他们具有 TBDs 的临床表现和短端粒，这些与相同的单等位基因变异 c.767A>G；Y256C 有关。尽管复制蛋白 A2（RPA2）突变不影响 RPA 的单链 DNA 结合和 G-四链体解旋特性，但该突变降低了 RPA2 与泛素连接酶 RFWD3 的亲和力，并降低了 RPA 的泛素化。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 的激活，但会导致短而功能失调的端粒。最后，两名患者在血液细胞的亚群中获得了已知可对抗端粒加速缩短的基因或基因启动子的体细胞遗传挽救事件。总的来说，我们的研究表明，基因中的变异代表了 TBDs 的一种新的遗传原因。我们的结果进一步支持了 RPA 复合物在调节人类端粒长度和稳定性方面的基本作用。
