1. Heterozygous RPA2 variant as a novel genetic cause of telomere biology disorders.
- Author
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Kochman R, Ba I, Yates M, Pirabakaran V, Gourmelon F, Churikov D, Laffaille M, Kermasson L, Hamelin C, Marois I, Jourquin F, Braud L, Bechara M, Lainey E, Nunes H, Breton P, Penhouet M, David P, Géli V, Lachaud C, Maréchal A, Revy P, Kannengiesser C, Saintomé C, and Coulon S
- Subjects
- Humans, Heterozygote, Male, Female, Shelterin Complex, Telomere Shortening genetics, Mutation, Telomerase genetics, Telomerase metabolism, Ubiquitination genetics, Ubiquitin-Protein Ligases genetics, Replication Protein A genetics, Replication Protein A metabolism, Telomere genetics, Telomere-Binding Proteins genetics, Telomere-Binding Proteins metabolism
- Abstract
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., (© 2024 Kochman et al.; Published by Cold Spring Harbor Laboratory Press.)
- Published
- 2024
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