Lee, Lara, Perez Oliva, Ana Belen, Martinez-Balsalobre, Elena, Churikov, Dmitri, Peter, Joshua, Rahmouni, Dalicya, Audoly, Gilles, Azzoni, Violette, Audebert, Stephane, Camoin, Luc, Mulero, Victoriano, Cayuela, Maria, Kulathu, Yogesh, Geli, Vincent, Lachaud, Christophe, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospital Clínico Universitario Virgen de la Arrixaca = University Hospital Virgen de la Arrixaca [Murcia], Universidad de Murcia, University of Dundee, lachaud, christophe, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Hospital Clínico Universitario Virgen de la Arrixaca [Murcia, Spain], and GELI, Vincent
Description, UF-MRE11 recruits PP1-a to dephosphorylate NBS1 regulating Apollo recruitment and preserving telomere leading strand., Ubiquitin-fold modifier 1 (UFM1) is involved in neural and erythroid development, yet its biological roles in these processes are unknown. Here, we generated zebrafish models deficient in Ufm1 and Ufl1 that exhibited telomere shortening associated with developmental delay, impaired hematopoiesis and premature aging. We further report that HeLa cells lacking UFL1 have instability of telomeres replicated by leading-strand synthesis. We uncover that MRE11 UFMylation is necessary for the recruitment of the phosphatase PP1-α leading to dephosphorylation of NBS1. In the absence of UFMylation, NBS1 remains phosphorylated, thereby reducing MRN recruitment to telomeres. The absence of MRN at telomeres favors the formation of the TRF2-Apollo/SNM1 complex consistent with the loss of leading telomeres. These results suggest that MRE11-UFMylation may serve as module to recruit PP1-α. Last, zebrafish expressing Mre11 that cannot be UFMylated phenocopy Ufm1-deficient zebrafish, demonstrating that UFMylation of MRE11 is a previously undescribed evolutionarily conserved mechanisms regulating telomere length.