title: DNA lesions induced by replication stress trigger mitotic aberration and tetraploidy development.
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.
authors.affiliation: Department of Pathological Biochemistry, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Ichijima
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Yoshioka
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Yoshioka
authors.forename: Keitaro
authors.initials: K
authors.lastname: Shinohe
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Fujimori
authors.forename: Junya
authors.initials: J
authors.lastname: Unno
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Takagi
authors.forename: Hidemasa
authors.initials: H
authors.lastname: Goto
authors.forename: Masaki
authors.initials: M
authors.lastname: Inagaki
authors.forename: Shuki
authors.initials: S
authors.lastname: Mizutani
authors.forename: Hirobumi
authors.initials: H
authors.lastname: Teraoka
mesh_terms: D000818:Animals; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D004249:DNA Damage; D004261:DNA Replication; D051379:Mice; D008938:Mitosis; D009857:Oncogenes; D011123:Polyploidy; D016196:S Phase