Biology subjects

Martinez-Balsalobre, E.

Publications and source records attributed to Martinez-Balsalobre, E..

3 recordsLinked to original sources

bioRxiv2021

Telomerase and Alternative Lengthening of Telomeres coexist in the regenerating zebrafish caudal fins

Telomeres are essential for chromosome protection and genomic stability, and telomerase function is critical to organ homeostasis. Zebrafish has become a useful vertebrate model for understanding the cellular and molecular mechanisms of regeneration. The regeneration capacity of the caudal fin of wild-type zebrafish is not affected by repetitive amputation, but the behavior of telomeres during this process has not yet been studied. In this study, the regeneration process was characterized in a telomerase deficient zebrafish model. Moreover, the regenerative capacity after repetitive amputations and at different ages was studied. Regenerative efficiency decreases with aging in all genotypes and surprisingly, telomere length is maintained even in telomerase deficient genotypes. Our results suggest that telomere length can be maintained by the regenerating cells through the recombination-mediated Alternative Lengthening of Telomeres (ALT) pathway, which is likely to support high rates of cell proliferation during the tailfin regeneration process. As far as we know, this is the first animal model to study ALT mechanism in regeneration, which opens a wealth of possibilities to study new treatments of ALT dependent processes.

genetics↗

bioRxiv2020

TERT-mediated induction of MIR500A contributes to tumor invasiveness by targeting Hedgehog pathway

The classical activity of telomerase (TERT) is to maintain telomere homeostasis, ensuring chromosome stability and cellular proliferation. However, increasing evidences of telomere-independent human TERT functions have been lastly obtained. We report here that TERT directly binds to the TCF binding elements (TBE) located upstream the oncomiR MIR500A inducing its expression and promoting cancer invasiveness. This function is independent of telomerase activity, since catalytic inactive TERT also induces MIR500A expression and telomerase inhibitors directed against TERT, but not to its RNA component TERC, inhibit telomerase-induced MIR500A expression and cancer invasiveness. Mechanistically, telomerase-induced MIR500A down-regulates key genes of the Hedgehog signaling pathway, namely patched 1 (PTCH1), Gli family zinc finger 3 (GLI3) and cullin 3 (CUL3), increasing tumor invasiveness. Our results show a crucial role of the TERT/MIR500A/Hedgehog axis is tumor aggressiveness, pointing out to the relevance of inhibiting the extracurricular functions of telomerase to fight cancer.

cancer biology↗

bioRxiv2019

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

Genetic studies using knockout mouse models provide strong evidence for the essential role of the ubiquitin-like protein UFM1 for hematopoiesis, especially erythroid development, yet its biological roles in this process are largely unknown. Here we have identified a UFL1-dependent UFMylation of the MRE11 nuclease on the K281 and K282 residues. We show that Hela cells lacking the specific UFM1 E3 ligase display severe telomere shortening. We further demonstrate either by deleting UFM1 or by mutating MRE11 UFMylation sites that preventing MRE11 UFMylation impacts its interaction with the telomere protein TRF2. However, the MRE11 function in double-strand-break repair remains intact. We validate these results in vivo by showing that Zebrafish knockouts for the genes ufl1 and ufm1 have shorter telomeres in hematopoietic cells. Here we present UFMylation has a new mechanisms of regulation for telomere length maintenance with a role in hematopoiesis. Key pointsModification of MRE11 by UFM1 regulates telomere maintenance and cell death in HSCs Scientific categoryUFMylation, telomere maintenance, hematopoietic stem cell survival.

molecular biology↗