Non-canonical telomere protection role of FOXO3a of human skeletal muscle cells regulated by the TRF2-redox axis.
Maria Sol Jacome BurbanoJérôme D RobinSerge BauwensMarjorie MartinEmma DonatiLucia MartínezPeipei LinSabrina SacconiFrédérique MagdinierEric GilsonPublished in: Communications biology (2023)
Telomeric repeat binding factor 2 (TRF2) binds to telomeres and protects chromosome ends against the DNA damage response and senescence. Although the expression of TRF2 is downregulated upon cellular senescence and in various aging tissues, including skeletal muscle tissues, very little is known about the contribution of this decline to aging. We previously showed that TRF2 loss in myofibers does not trigger telomere deprotection but mitochondrial dysfunction leading to an increased level of reactive oxygen species. We show here that this oxidative stress triggers the binding of FOXO3a to telomeres where it protects against ATM activation, revealing a previously unrecognized telomere protective function of FOXO3a, to the best of our knowledge. We further showed in transformed fibroblasts and myotubes that the telomere properties of FOXO3a are dependent on the C-terminal segment of its CR2 domain (CR2C) but independent of its Forkhead DNA binding domain and of its CR3 transactivation domain. We propose that these non-canonical properties of FOXO3a at telomeres play a role downstream of the mitochondrial signaling induced by TRF2 downregulation to regulate skeletal muscle homeostasis and aging.
Keyphrases
- transcription factor
- dna binding
- skeletal muscle
- dna damage response
- signaling pathway
- oxidative stress
- pi k akt
- endothelial cells
- dna damage
- induced apoptosis
- insulin resistance
- reactive oxygen species
- dna repair
- gene expression
- poor prognosis
- healthcare
- cell cycle arrest
- cell proliferation
- binding protein
- adipose tissue
- induced pluripotent stem cells
- type diabetes
- ischemia reperfusion injury
- dna methylation
- metabolic syndrome
- stress induced
- long non coding rna
- heat shock protein