UFMylation of MRE11 is essential for telomere length maintenance and hematopoietic stem cell survival

Lara Lee, Ana Belen Perez Oliva, Elena Martinez-Balsalobre, Dmitri Churikov, Joshua Peter, Dalicya Rahmouni, Gilles Audoly, Violette Azzoni, Stephane Audebert, Luc Camoin, Victoriano Mulero, Maria L. Cayuela, Yogesh Kulathu, Vincent Geli, Christophe Lachaud (Lead / Corresponding author)

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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.

Original languageEnglish
Article numbereabc7371
Number of pages15
JournalScience Advances
Issue number39
Publication statusPublished - 24 Sept 2021


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