{"id":5725,"date":"2025-01-28T15:14:15","date_gmt":"2025-01-28T14:14:15","guid":{"rendered":"https:\/\/crcm-marseille.fr\/uncategorized\/coulon-team-identifies-heterozygous-rpa2-variant-as-new-cause-of-telomere-biology-disorders\/"},"modified":"2025-04-23T16:30:40","modified_gmt":"2025-04-23T14:30:40","slug":"coulon-team-identifies-heterozygous-rpa2-variant-as-new-cause-of-telomere-biology-disorders","status":"publish","type":"post","link":"https:\/\/crcm-marseille.fr\/en\/scientific-publication\/coulon-team-identifies-heterozygous-rpa2-variant-as-new-cause-of-telomere-biology-disorders\/","title":{"rendered":"Coulon team identifies heterozygous RPA2 variant as new cause of telomere biology disorders"},"content":{"rendered":"\n<p><strong>Abstract<\/strong>: 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&gt;G; Y256C in <em>RPA2<\/em> 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 <em>POT1<\/em> genes or <em>TERT<\/em> promoters known to counteract the accelerated telomere shortening. Collectively, our study indicates that variants in <em>RPA2<\/em> 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.     <\/p>\n\n<p>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, G\u00e9li V, Lachaud C, Mar\u00e9chal A, Revy P, Kannengiesser C, Saintom\u00e9 C, Coulon S. <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/39231615\/\">Heterozygous <em>RPA2<\/em> variant as a novel genetic cause of telomere biology disorders. <\/a>Genes Dev. 2024 Sep 19;38(15-16):755-771.   <\/p>\n\n<div style=\"height:50px\" aria-hidden=\"true\" class=\"wp-block-spacer\"><\/div>\n\n<div class=\"wp-block-buttons is-content-justification-center is-layout-flex wp-container-core-buttons-is-layout-16018d1d wp-block-buttons-is-layout-flex\">\n<div class=\"wp-block-button\"><a class=\"wp-block-button__link wp-element-button\" href=\"https:\/\/crcm-marseille.fr\/departement-genome-integrity\/equipe-telomeres-et-chromatine-departement-genome-integrity\/\">Find out more about the Coulon team<\/a><\/div>\n<\/div>\n\n<p><\/p>\n","protected":false},"excerpt":{"rendered":"<p>Published in <i>Genes &amp; Development<\/i>, the Coulon team&#8217;s study identifies a heterozygous variant of RPA2 as a new cause of disorders in telomere biology, impacting their stability and regulation.<\/p>\n","protected":false},"author":3,"featured_media":5475,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_tec_requires_first_save":true,"_EventAllDay":false,"_EventTimezone":"","_EventStartDate":"","_EventEndDate":"","_EventStartDateUTC":"","_EventEndDateUTC":"","_EventShowMap":false,"_EventShowMapLink":false,"_EventURL":"","_EventCost":"","_EventCostDescription":"","_EventCurrencySymbol":"","_EventCurrencyCode":"","_EventCurrencyPosition":"","_EventDateTimeSeparator":"","_EventTimeRangeSeparator":"","_EventOrganizerID":[],"_EventVenueID":[],"_OrganizerEmail":"","_OrganizerPhone":"","_OrganizerWebsite":"","_VenueAddress":"","_VenueCity":"","_VenueCountry":"","_VenueProvince":"","_VenueState":"","_VenueZip":"","_VenuePhone":"","_VenueURL":"","_VenueStateProvince":"","_VenueLat":"","_VenueLng":"","_VenueShowMap":false,"_VenueShowMapLink":false,"_tribe_blocks_recurrence_rules":"","_tribe_blocks_recurrence_description":"","_tribe_blocks_recurrence_exclusions":"","footnotes":""},"categories":[200,203,207],"tags":[],"class_list":["post-5725","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-genome-integrity-department","category-scientific-publication","category-the-coulon-team"],"yoast_head":"<!-- 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stability and regulation.\" \/>\n<meta property=\"og:url\" content=\"https:\/\/crcm-marseille.fr\/en\/scientific-publication\/coulon-team-identifies-heterozygous-rpa2-variant-as-new-cause-of-telomere-biology-disorders\/\" \/>\n<meta property=\"og:site_name\" content=\"CRCM\" \/>\n<meta property=\"article:published_time\" content=\"2025-01-28T14:14:15+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2025-04-23T14:30:40+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/crcm-marseille.fr\/wp-content\/uploads\/2025\/01\/Coulon-News-2.jpg\" \/>\n\t<meta property=\"og:image:width\" content=\"760\" \/>\n\t<meta property=\"og:image:height\" content=\"453\" \/>\n\t<meta property=\"og:image:type\" content=\"image\/jpeg\" \/>\n<meta name=\"author\" content=\"L\u00e9a Girard\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:label1\" content=\"Written by\" \/>\n\t<meta name=\"twitter:data1\" content=\"L\u00e9a Girard\" 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