Abstract
Ferroptosis is a novel form of iron-dependent cell death characterized by lipid peroxidation. While the importance and disease relevance of ferroptosis are gaining recognition, much remains unknown about its interaction with other biological processes and pathways. Recently, several studies have identified intricate and complicated interplay between ferroptosis, ionizing radiation (IR), ATM (ataxia–telangiectasia mutated)/ATR (ATM and Rad3-related), and tumor suppressor p53, which signifies the participation of the DNA damage response (DDR) in iron-related cell death. DDR is an evolutionarily conserved response triggered by various DNA insults to attenuate proliferation, enable DNA repairs, and dispose of cells with damaged DNA to maintain genome integrity. Deficiency in proper DDR in many genetic disorders or tumors also highlights the importance of this pathway. In this review, we will focus on the biological crosstalk between DDR and ferroptosis, which is mediated mostly via noncanonical mechanisms. For clinical applications, we also discuss the potential of combining ionizing radiation and ferroptosis-inducers for synergistic effects. At last, various ATM/ATR inhibitors under clinical development may protect ferroptosis and treat many ferroptosis-related diseases to prevent cell death, delay disease progression, and improve clinical outcomes.
Highlights
FSP1 catalyzes the formation of reduced coenzyme Q10 (CoQ10 ), which serves as a radical-trapping antioxidant to neutralize lipid peroxidation and reactive oxygen species (ROS) and peroxidation
ATR is identified based on its sequence homology to ATM, featuring its ability to prevent abnormal cell division or aneuploidy when activated during DNA damage [27]
ATM phosphorylates MDM2 to compromise its ligase activity and p53 ubiquitination [58,59], while ATR attenuates p53 nuclear export by phosphorylation of MDM2 at S407 [60]. This ATR/ATM–MDM2/MDMX–p53 axis is essential for the DNA damage-induced p53 stabilization and transcriptional control to trigger cell-cycle arrest, DNA repair, and apoptosis events as part of canonical DNA damage response (DDR) phenotypic responses
Summary
Programmed cell death (PCD) plays a critical role in tissue homeostasis and many pathological conditions. FSP1 catalyzes the formation of reduced coenzyme Q10 (CoQ10 ), which serves as a radical-trapping antioxidant to neutralize lipid peroxidation and reactive oxygen species (ROS) and peroxidation This novel mechanism of ferroptosis protection may provide additional insights and therapeutic opportunities. The central sensors and upstream DDR kinases include the ATM (ataxia–telangiectasia mutated), ATR (ATM and Rad3-related), and DNA–PKs (DNA dependent protein kinase). These DDR kinases regulate the levels and activities of various effector proteins [23], including the guardian of genome integrity, p53, and its critical negative regulators, MDM2 (mouse double minute 2) and MDMX (murine double minute X)
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