Loss of Rb proteins causes genomic instability in the absence of mitogenic signaling
- Tanja van Harn1,5,
- Floris Foijer1,2,5,
- Marcel van Vugt3,
- Ruby Banerjee2,
- Fentang Yang2,
- Anneke Oostra4,
- Hans Joenje4 and
- Hein te Riele1,6
- 1Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands;
- 2Wellcome Trust Genome Campus, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, United Kingdom;
- 3Department of Medical Oncology, Groningen Medical Centre, Groningen 9713 GZ, The Netherlands;
- 4Department of Clinical Genetics, VU University Medical Center, Amsterdam 1081 BT, The Netherlands
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↵5 These authors contributed equally to this work.
Abstract
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.
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Footnotes
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↵6 Corresponding author.
E-MAIL h.t.riele{at}nki.nl; FAX 31-20-6691383.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.580710.
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Supplemental material is available at http://www.genesdev.org.
- Received February 17, 2010.
- Accepted May 4, 2010.
- Copyright © 2010 by Cold Spring Harbor Laboratory Press