Loss of Rb proteins causes genomic instability in the absence of mitogenic signaling.
Loss of G1/S control is a hallmark of cancer, and is often caused by inactivation of the retinoblastoma pathway. However, mouse embryonic fibroblasts lacking the retinoblastoma genes RB1, p107, and p130 (TKO MEFs) are still subject to cell cycle control: Upon mitogen deprivation, they enter and complete S phase, but then firmly arrest in G2. We now show that G2-arrested TKO MEFs have accumulated DNA damage. Upon mitogen readdition, cells resume proliferation, although only part of the damage is repaired. As a result, mitotic cells show chromatid breaks and chromatid cohesion defects. These aberrations lead to aneuploidy in the descendent cell population. Thus, our results demonstrate that unfavorable growth conditions can cause genomic instability in cells lacking G1/S control. This mechanism may allow premalignant tumor cells to acquire additional genetic alterations that promote tumorigenesis.
van Harn
Tanja
T
Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Foijer
Floris
F
van Vugt
Marcel
M
Banerjee
Ruby
R
Yang
Fentang
F
Oostra
Anneke
A
Joenje
Hans
H
te Riele
Hein
H
D000782:Aneuploidy; D000818:Animals; D002453:Cell Cycle; D049109:Cell Proliferation / Q000187:drug effects; D002503:Centromere; D053903:DNA Breaks, Double-Stranded; D056915:DNA Copy Number Variations; D005347:Fibroblasts / Q000166:cytology; D042822:Genomic Instability; D051379:Mice; D008934:Mitogens / Q000494:pharmacology / Q000502:physiology*; D016160:Retinoblastoma Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D050720:Retinoblastoma-Like Protein p107 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D050717:Retinoblastoma-Like Protein p130 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D008934:Mitogens; C489485:Rbl1 protein, mouse; C493838:Rbl2 protein, mouse; D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130