DNA Lesions Induced by Replication Stress Trigger Mitotic Aberration
and Tetraploidy Development |
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Authors: | Yosuke Ichijima Ken-ichi Yoshioka Yoshiko Yoshioka Keitaro Shinohe Hiroaki Fujimori Junya Unno Masatoshi Takagi Hidemasa Goto Masaki Inagaki Shuki Mizutani Hirobumi Teraoka |
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Institution: | 1. Department of Pathological Biochemistry, Medical Research Institute,
Tokyo Medical and Dental University, Tokyo, Japan.; 2. Biochemistry Division, National Cancer Center Research Institute, Tokyo,
Japan.; 3. Department of Pediatrics and Developmental Biology, Tokyo Medical and
Dental University Graduate School, Tokyo, Japan.; 4. Division of Biochemistry, Aichi Cancer Center Research Institute, Nagoya,
Japan.;Roswell Park Cancer Institute, United States of America |
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Abstract: | During tumorigenesis, cells acquire immortality in association with the
development of genomic instability. However, it is still elusive how genomic
instability spontaneously generates during the process of tumorigenesis. Here,
we show that precancerous DNA lesions induced by oncogene acceleration, which
induce situations identical to the initial stages of cancer development, trigger
tetraploidy/aneuploidy generation in association with mitotic aberration.
Although oncogene acceleration primarily induces DNA replication stress and the
resulting lesions in the S phase, these lesions are carried over into the M
phase and cause cytokinesis failure and genomic instability. Unlike directly
induced DNA double-strand breaks, DNA replication stress-associated lesions are
cryptogenic and pass through cell-cycle checkpoints due to limited and
ineffective activation of checkpoint factors. Furthermore, since damaged M-phase
cells still progress in mitotic steps, these cells result in chromosomal
mis-segregation, cytokinesis failure and the resulting tetraploidy generation.
Thus, our results reveal a process of genomic instability generation triggered
by precancerous DNA replication stress. |
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