TY - JOUR
T1 - Loss of p53-mediated cell-cycle arrest, senescence and apoptosis promotes genomic instability and premature aging
AU - Li, Tongyuan
AU - Liu, Xiangyu
AU - Jiang, Le
AU - Manfredi, James
AU - Zha, Shan
AU - Gu, Wei
N1 - Funding Information:
This work was supported by the National Cancer Institute of the National Institutes of Health under Award 5R01CA172023, 5RO1CA169246, and 5RO1CA085533 to W.G. 2P01CA080058 to W.G. and J. M., and R01CA184187 to S.Z. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. X.L and S.Z are fellow and scholar of Leukemia Lymphoma Society respecitively.
PY - 2016/3/15
Y1 - 2016/3/15
N2 - 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.
AB - 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.
KW - Acetylation
KW - Ferroptosis
KW - Genomic instability
KW - Tumor suppression
KW - p53
UR - http://www.scopus.com/inward/record.url?scp=84962835198&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.7864
DO - 10.18632/oncotarget.7864
M3 - Article
C2 - 26943586
AN - SCOPUS:84962835198
SN - 1949-2553
VL - 7
SP - 11838
EP - 11849
JO - Oncotarget
JF - Oncotarget
IS - 11
ER -