PLoS ONE (Jan 2011)

Onset of quiescence following p53 mediated down-regulation of H2AX in normal cells.

  • Yuko Atsumi,
  • Hiroaki Fujimori,
  • Hirokazu Fukuda,
  • Aki Inase,
  • Keitaro Shinohe,
  • Yoshiko Yoshioka,
  • Mima Shikanai,
  • Yosuke Ichijima,
  • Junya Unno,
  • Shuki Mizutani,
  • Naoto Tsuchiya,
  • Yoshitaka Hippo,
  • Hitoshi Nakagama,
  • Mitsuko Masutani,
  • Hirobumi Teraoka,
  • Ken-ichi Yoshioka

DOI
https://doi.org/10.1371/journal.pone.0023432
Journal volume & issue
Vol. 6, no. 8
p. e23432

Abstract

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Normal cells, both in vivo and in vitro, become quiescent after serial cell proliferation. During this process, cells can develop immortality with genomic instability, although the mechanisms by which this is regulated are unclear. Here, we show that a growth-arrested cellular status is produced by the down-regulation of histone H2AX in normal cells. Normal mouse embryonic fibroblast cells preserve an H2AX diminished quiescent status through p53 regulation and stable-diploidy maintenance. However, such quiescence is abrogated under continuous growth stimulation, inducing DNA replication stress. Because DNA replication stress-associated lesions are cryptogenic and capable of mediating chromosome-bridge formation and cytokinesis failure, this results in tetraploidization. Arf/p53 module-mutation is induced during tetraploidization with the resulting H2AX recovery and immortality acquisition. Thus, although cellular homeostasis is preserved under quiescence with stable diploidy, tetraploidization induced under growth stimulation disrupts the homeostasis and triggers immortality acquisition.