LSD1-mediated demethylation of the DNA damage response factor ATM promotes senescence and organ aging
Yingying Zhang, Chen Yu, Xiaoqin Zhang, Linda Xiaoyan Li, Alice Shasha Cheng, Xiaogang Li
Yingying Zhang, Chen Yu, Xiaoqin Zhang, Linda Xiaoyan Li, Alice Shasha Cheng, Xiaogang Li
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Research Article Aging Cell biology

LSD1-mediated demethylation of the DNA damage response factor ATM promotes senescence and organ aging

Abstract

Aging occurs heterogeneously across organs, leading to progressive tissue dysfunction. Cellular senescence is a stress response triggered by age-associated insults, yet the mechanisms regulating senescence and organ aging remain incompletely understood. Here, we defined a role for lysine-specific demethylase 1 (LSD1) in DNA damage–mediated senescence and organ aging. LSD1 was upregulated in aged organs and senescent cells. In response to natural aging or ionizing radiation–induced DNA damage, LSD1 interacted with and demethylated ATM at lysine 3,016, as confirmed using a newly generated ATM-K3016me antibody. This modification sustained ATM phosphorylation, amplified DNA damage signaling, and delayed checkpoint recovery, promoting senescence and organ aging. Inhibition of LSD1 accelerated ATM dephosphorylation via WIP1, enhanced DNA repair, reduced senescence and DNA damage, and prevented irradiation-induced hair graying. Elimination of senescent cells with senolytics reduced LSD1 protein in aged organs, indicating a feedback loop between LSD1 and senescence. Mechanistically, LSD1 underwent autophagosome-lysosome degradation through interaction with LC3 and Beclin1, and autophagy impairment during DNA damage contributed to LSD1 accumulation in senescent cells. This study revealed LSD1 as a key regulator of DNA damage–induced senescence and organ aging and suggested that targeting LSD1 may attenuate senescence, delay organ aging, and prevent hair graying.

Authors

Yingying Zhang, Chen Yu, Xiaoqin Zhang, Linda Xiaoyan Li, Alice Shasha Cheng, Xiaogang Li

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Working model. Cellular senescence is marked by a state of stable cell c...
Cellular senescence is marked by a state of stable cell cycle arrest and plays a crucial role in aging and age-related diseases. DNA damage, a fundamental driver of cellular senescence, influences all hallmarks of aging. DNA damage response (DDR) is regulated either by histone modifications or by their interactions with and modifications of nonhistone substrates. In this study, we define the roles of lysine-specific histone demethylase 1 (LSD1) in senescence and aging and mechanistically address (a) a crosstalk of LSD1 and ATM activation, and (b) how the stability of LSD1 is regulated by autophagy during senescence and organ aging. Aging, irradiation or other factors led to increased expression of LSD1. In response to DNA damage, upregulation of LSD1 results in: (a) LSD1 interaction with and demethylation of ATM at its Lysine-3016 (K3016), (b) LSD1 mediated demethylation of ATM and inhibition of its interaction with WIP1, which blocks DNA damage repair and promotes cellular senescence, (c) aging-induced impairment of autophagy, leading to a reduced degradation of LSD1, (d) LC3 and Beclin1 interaction with LSD1, subjecting it to autophagy-mediated degradation. Thus, treatment with senolytic drugs (Dasatinib and Quercetin) to eliminate senescent cells reduces LSD1 expression, and inhibition of LSD1 by its specific inhibitor ORY-1001 ameliorates cellular senescence and organ aging.