mEst1A (mouse Ever Shorter Telomeres 1A) regulates telomere length and RNA quality control in murine stem cells
FacultiesFakultät für Naturwissenschaften
Est1A/SMG6 controls telomere elongation by mediating telomerase recruitment. In addition, it is an essential component of the endonucleolytic branch of the Nonsense-mediated mRNA decay (NMD) pathway, which controls RNA quality by eliminating mRNAs that harbour premature termination codons (PTC). In vivo function of Est1A/SMG6 has not been investigated in genetic mouse models. Here, we show in conditional knockout mice that germ line deletion of Est1A/SMG6 leads to embryonic lethality. Cre-mediated deletion of mEst1A in adult mice led to telomere shortening in small intestine comparable to the first generation of TERC deficient mice. Moreover, depletion of mEst1A induced a variety of phenotypes that were associated with defects in NMD including mitotic arrest in liver after partial hepatectomy, rapid loss of cellularity in bone marrow, defect in thymocytes maturation, and accumulation of nonsense mediated mRNAs. Our studies revealed that Est1 deletion exhibits selective toxicity in hematopoietic stem cells (HSCs) but not in intestinal, muscle or liver stem cells (ISCs, MSCs, LSCs). Gene expression analysis revealed an increase in RNAs that are controlled by NMD in both HSCs and ISCs. Together, these results indicate that mEst1A has a role in telomerase regulation in vivo. In addition, mEst1A is important for NMD in different stem cell compartments in adult mice. Given that telomere shortening in Est1 knockout tissues is not associated with telomere dysfunction or an activation of DNA damage checkpoints, these results suggests that loss of NMD function leads to selective toxicity in HSCs but not in other stem cell compartments. Further analysis of mEst1A deficient mice could help to identify checkpoints that mediate stem cell depeletion in response to an accumulation of nonsense RNAs. In a broader context, it would be interesting to analyze whether NMD deficiencies contribute to stem cell exhaustion or transformation during aging and cancer formation. Die Online-Version wurde zurückgezogen. Bitte verwenden Sie die publizierte gedruckte Version, die sich im Bestand des kiz befindet und auch via Fernleihe zugänglich ist.
Subject HeadingsTelomerase [GND]
Hematopoietic stem cells [MeSH]