Distinct roles of Nrf1 and Nrf2 in coordinately controlling the anti-ageing response

Nuclear factor erythroid-derived 2-like 1(Nrf1,encoded by Nfe2l1), an essential transcription factor of the cap'n'collar basic-region leucine zipper(CNC-bZIP)family, is highly conserved with its homologous Nuclear factor erythroid-derived 2-like 2(Nrf2,encoded by Nfe2l2). Of note, Nrf1 possesses a remarkable anti-senescence potential, but it has not been comprehensively characterized to date. Conversely, Nrf1α-/- cells undergoing senescence display hallmarks of senescence, comprising heightened activity of senescence-associated β-galactosidase, decreased cell vitality, cell growth arrest, and increased expression of the senescence-associated secretory phenotype. Further investigation showed cellular senescence in Nrf1α-/- cells is not a consequence of Nrf2 accumulation. On the contrary, Nrf2 could alleviate, but not halt or reverse, senescence of Nrf1α-/- cells. This is predominantly attributable to the fact that, different from Nrf2, the deficiency of Nrf1 brings about activation of both p21 and RB pathwanys independently of p53, but disrupts STAG2- and SMC3-dependent chromosomal homeostasis so to drive cell senescence. Here, we discover the significant anti-senescence capacity of Nrf1 and highlight two mechanisms underlying the protective function of Nrf1, which stem from its response to stress and its role in maintaining cellular homeostasis. ### Competing Interest Statement The authors have declared no competing interest.