Endogenous p53 inhibitor TIRR dissociates systemic metabolic health from oncogenic activity
Abstract
It is unclear whether metabolic health corresponds to reduced oncogenesis or vice versa. We study Tudor-interacting repair regulator (TIRR), an inhibitor of p53 binding protein 1 (53BP1)-mediated p53 activation, and the physiological consequences of enhancing tumor suppressor activity. Deleting TIRR selectively activates p53, significantly protecting against cancer but leading to a systemic metabolic imbalance in mice. TIRR-deficient mice are overweight and insulin resistant, even under normal chow diet. Similarly, reduced TIRR expression in human adipose tissue correlates with higher BMI and insulin resistance. Despite the metabolic challenges, TIRR loss improves p53 heterozygous (p53 HET ) mouse survival and correlates with enhanced progression-free survival in patients with various p53 HET carcinomas. Finally, TIRR's oncoprotective and metabolic effects are dependent on p53 and lost upon p53 deletion in TIRR-deficient mice, with glucose homeostasis and orexigenesis being primarily regulated by TIRR expression in the adipose tissue and the CNS, respectively, as evidenced by tissue-specific models. In summary, TIRR deletion provides a paradigm of metabolic deregulation accompanied by reduced oncogenesis.
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BibTeX
@article{tsaousidou2026endogenous,
title = {{Endogenous p53 inhibitor TIRR dissociates systemic metabolic health from oncogenic activity}},
author = {Eva Tsaousidou and Jędrzej Chrzanowski and Pascal Drané and Grace Lee and Nadine Bahour and Zeqiu Branden Wang and Shijun Deng and Zhe Cao and Kaimeng Huang and Yizhou He and Mateusz Kaminski and Dominika Michalek and Ekin Güney and Kalindi Parmar and Wojciech Fendler and Dipanjan Chowdhury and Gökhan Hotamışlıgil},
journal = {Cell Reports},
year = {2026},
month = oct,
doi = {10.1016/j.celrep.2024.114337},
url = {https://hal.science/hal-05829502v1},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Endogenous p53 inhibitor TIRR dissociates systemic metabolic health from oncogenic activity
AU - Eva Tsaousidou
AU - Jędrzej Chrzanowski
AU - Pascal Drané
AU - Grace Lee
AU - Nadine Bahour
AU - Zeqiu Branden Wang
AU - Shijun Deng
AU - Zhe Cao
AU - Kaimeng Huang
AU - Yizhou He
AU - Mateusz Kaminski
AU - Dominika Michalek
AU - Ekin Güney
AU - Kalindi Parmar
AU - Wojciech Fendler
AU - Dipanjan Chowdhury
AU - Gökhan Hotamışlıgil
PY - 2026
DA - 2026/10/21
JO - Cell Reports
DO - 10.1016/j.celrep.2024.114337
UR - https://hal.science/hal-05829502v1
AB - It is unclear whether metabolic health corresponds to reduced oncogenesis or vice versa. We study Tudor-interacting repair regulator (TIRR), an inhibitor of p53 binding protein 1 (53BP1)-mediated p53 activation, and the physiological consequences of enhancing tumor suppressor activity. Deleting TIRR selectively activates p53, significantly protecting against cancer but leading to a systemic metabolic imbalance in mice. TIRR-deficient mice are overweight and insulin resistant, even under normal chow diet. Similarly, reduced TIRR expression in human adipose tissue correlates with higher BMI and insulin resistance. Despite the metabolic challenges, TIRR loss improves p53 heterozygous (p53 HET ) mouse survival and correlates with enhanced progression-free survival in patients with various p53 HET carcinomas. Finally, TIRR's oncoprotective and metabolic effects are dependent on p53 and lost upon p53 deletion in TIRR-deficient mice, with glucose homeostasis and orexigenesis being primarily regulated by TIRR expression in the adipose tissue and the CNS, respectively, as evidenced by tissue-specific models. In summary, TIRR deletion provides a paradigm of metabolic deregulation accompanied by reduced oncogenesis.
SN - 2211-1247
SN - 2211-1247
ER -