Temporal Dynamic Regulation of Autophagy and Senescence Induction in Response to Radiation Exposure

  • Miho Noguchi
    Institute for Quantum Life Science, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba-shi, Chiba 263-8555, Japan
  • Tomokazu Ihara
    Institute for Quantum Life Science, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba-shi, Chiba 263-8555, Japan
  • Keiji Suzuki
    Atomic Bomb Disease Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki-shi, Nagasaki 852-8523, Japan
  • Akinari Yokoya
    Institute for Quantum Life Science, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba-shi, Chiba 263-8555, Japan

Search this article

Description

Autophagy and senescence are closely related cellular responses to genotoxic stress, and play significant roles in the execution of cellular responses to radiation exposure. However, little is known about their interplay in the fate-decision of cells receiving lethal doses of radiation. Here, we report that autophagy precedes the establishment of premature senescence in normal human fibroblasts exposed to lethal doses of radiation. Activation of the p53-dependent DNA damage response caused sustained dephosphorylation of RB proteins and consequent cell cycle arrest, concurrently with Ulk1 dephosphorylation at Ser638 by PPM1D, which promoted autophagy induction 1-2 days after irradiation. In addition, mitochondrial fragmentation became obvious 1-2 days after irradiation, and autophagy was further enhanced. However, Ulk1 levels decreased significantly after 2 days, resulting in lower LC3-II levels. An autophagic flux assay using chloroquine (CQ) also revealed that the flux in irradiated cells gradually decreased over 30 days. In contrast, lysosomal augmentation started at 1 day, became significantly upregulated after 5 days, and continued for over 30 days. After a rapid decrease in autophagy, p16 expression increased and senescence was established, but autophagic activity remained reduced. These results demonstrated that X-ray irradiation triggered two processes, autophagy and senescence, with the former being temporary and regulated by DNA damage response and mitophagy, and the latter being sustained and regulated by persistent cell cycle arrest. The interplay between autophagy and senescence seems to be essential for the proper implementation of the cellular response to radiation exposure.

Journal

References(44)*help

See more

Related Projects

See more

Details 詳細情報について

Report a problem

Back to top