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Aging-dependent dysregulation of EXOSC2 is maintained in cancer as a dependency

Skamagki, M.; Zhang, C.; Hacisuleyman, E.; Galleti, G.; Wu, C.; Vinagolu, R. K.; Cha, H.; Ata, D.; Kim, J.; Weiskittel, T.; Diop, M.; Aung, T.; Del Latto, M.; Kim, A. S.; Li, Z.; Miele, M.; Zhao, R.; Tang, L. H.; Hendrickson, R. C.; Romesser, P. B.; Smith, J. J.; Giannakakou, P.; Darnell, R. B.; Bott, M. J.; Li, H.; Kim, K.

2025-04-07 cell biology
10.1101/2025.04.04.647279 bioRxiv
Show abstract

Reprogramming of aged donor tissue cells into induced pluripotent stem cells (A-iPSC) preserved the epigenetic memory of aged-donor tissue, defined as genomic instability and poor tissue differentiation in our previous study. The unbalanced expression of RNA exosome subunits affects the RNA degradation complex function and is associated with geriatric diseases including premature aging and cancer progression. We hypothesized that the age-dependent progressive subtle dysregulation of EXOSC2 (exosome component 2) causes the aging traits (abnormal cell cycle and poor tissue differentiation). We used embryonic stem cells as a tool to study EXOSC2 function as the aging trait epigenetic memory determined in A-iPSC because these aging traits could not be studied in senesced aged cells or immortalized cancer cells. We found that the regulatory subunit of PP2A phosphatase, PPP2R5E, is a key target of EXOSC2 and this regulation is preserved in stem cells and cancer.

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