Abstract
Although p53-mediated cell cycle arrest, senescence and apoptosis are well accepted as major tumor suppression mechanisms, the loss of these functions does not directly lead to tumorigenesis, suggesting that the precise roles of these canonical activities of p53 need to be redefined. Here, we report that the cells derived from the mutant mice expressing p533KR, an acetylation-defective mutant that fails to induce cell-cycle arrest, senescence and apoptosis, exhibit high levels of aneuploidy upon DNA damage. Moreover, the embryonic lethality caused by the deficiency of XRCC4, a key DNA double strand break repair factor, can be fully rescued in the p533KR/3KR background. Notably, despite high levels of genomic instability, p533KR/3KRXRCC4−/− mice, unlike p53−/− XRCC4−/− mice, are not succumbed to pro-B-cell lymphomas. Nevertheless, p533KR/3KR XRCC4−/− mice display aging-like phenotypes including testicular atrophy, kyphosis, and premature death. Further analyses demonstrate that SLC7A11 is downregulated and that p53-mediated ferroptosis is significantly induced in spleens and testis of p533KR/3KRXRCC4−/− mice. These results demonstrate that the direct role of p53-mediated cell cycle arrest, senescence and apoptosis is to control genomic stability in vivo. Our study not only validates the importance of ferroptosis in p53-mediated tumor suppression in vivo but also reveals that the combination of genomic instability and activation of ferroptosis may promote aging-associated phenotypes.
Highlights
Given the importance of p53 in tumor development, genomic integrity and normal aging process, p53 activities are tightly regulated at multiple levels by a delicate network through various positive/negative regulators, cofactors, and a large number of posttranslational modifications, including phosphorylation, ubiquitination and acetylation [1,2,3,4,5]
Normal proliferating cells constantly cope with a variety of stress signals from both outside and inside such as replication stress, telomere shortening and reactive oxygen species (ROS) damage, and their genome integrity are inevitably damaged during proliferation, which can induce a p53mediated temporary arrest at cell cycle checkpoints to allow cells to correct possible defects, thereby avoiding the transmission of genetic lesions to daughter cells [39]
Since p53-mediated cell cycle arrest, apoptosis and senescence are abrogated in p533KR/3KR cells, it is not surprising that DNA damage is accumulated in these cells, leading to aneuploidy
Summary
Given the importance of p53 in tumor development, genomic integrity and normal aging process, p53 activities are tightly regulated at multiple levels by a delicate network through various positive/negative regulators, cofactors, and a large number of posttranslational modifications, including phosphorylation, ubiquitination and acetylation [1,2,3,4,5]. Loss of p53 function promotes chromosomal instability and wild-type p53 functions as a hub of DNA damage activated checkpoints and as a barrier against genomic instability [16, 17] In this context, p53 deficiency rescues embryonic lethality caused by the inactivation of many DNA double stand break(DSB) repair genes, such as XRCC4, by attenuating cell cycle checkpoint control, apoptosis and senescence to allow cell survival with genomic instabilities [18,19,20,21]. The p533KR/3KR mutant fail to induce p53-mediated cell cycle arrest, apoptotic cell death and senescence in response to DNA damage, yet still retains tumor suppression capacities, providing a unique tool to dissect the mechanisms of p53mediated activities in vivo [10]. These results redefine the role of p53-mediated cell-cycle arrest, senescence and apoptosis and have significance implications for the roles of p53-mediated ferroptosis in vivo
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