Abstract LB040: P62-mediated degradation of TIF-IA drives the senescence associated secretory phenotype

Abstract

Abstract Advanced age is one of the most significant risk factors for malignancy. One mechanism proposed for age-associated cancer risk is the accumulation of senescent cells in ageing tissue. These cells secrete a cocktail of pro-tumorigenic factors known as the senescence associated secretory phenotype (SASP). The SASP is driven by the NF-κB transcription factor. However, the initial triggers of NF-κB in senescence remain unclear. Here we describe a novel mechanism that triggers NF-κB and the SASP. Using multiple in vitro and in vivo models, we demonstrate accumulation and cytoplasmic to nuclear translocation of the PolI complex component, TIF-IA, upon senescence induction. siRNA knockdown revealed TIF-IA is not required for the cell cycle effects of senescence but is essential for transcription of SASP factors, nucleolar enlargement (a characteristic of senescence and marker of organismal ageing) and full senescence. We make the novel observation that in steady state, TIF-IA is targeted for autophagosomal degradation by the cargo receptor, p62, which is inhibited in senescence and promoted by inactivation of the DNA repair protein, ATM. Based on these data, we propose a model whereby the P62-TIF-IA interaction is lost downstream of DNA damage and ATM activation, which causes TIF-IA accumulation, the SASP and senescence. Using tissue from the well characterized nfkb1− / − mouse model of aging, and old and young mice, we show that TIF-IA accumulates in colonic mucosa with age, which is further enhance by nfkb1 deletion. These exciting new data identify a new role for TIF-IA and have considerable relevance to age-related cancer. Citation Format: Hazel Thoms, Lesley Stark. P62-mediated degradation of TIF-IA drives the senescence associated secretory phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB040.