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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-53286

Knobel, P A; Kotov, I N; Felley-Bosco, E; Stahel, R A; Marti, T M (2011). Inhibition of REV3 expression induces persistent DNA damage and growth arrest in cancer cells. Neoplasia, 13(10):961-970.

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Abstract

REV3 is the catalytic subunit of DNA translesion synthesis polymerase ζ. Inhibition of REV3 expression increases the sensitivity of human cells to a variety of DNA-damaging agents and reduces the formation of resistant cells. Surprisingly, we found that short hairpin RNA-mediated depletion of REV3 per se suppresses colony formation of lung (A549, Calu-3), breast (MCF-7, MDA-MB-231), mesothelioma (IL45 and ZL55), and colon (HCT116 +/-p53) tumor cell lines, whereas control cell lines (AD293, LP9-hTERT) and the normal mesothelial primary culture (SDM104) are less affected. Inhibition of REV3 expression in cancer cells leads to an accumulation of persistent DNA damage as indicated by an increase in phospho-ATM, 53BP1, and phospho-H2AX foci formation, subsequently leading to the activation of the ATM-dependent DNA damage response cascade. REV3 depletion in p53-proficient cancer cell lines results in a G(1) arrest and induction of senescence as indicated by the accumulation of p21 and an increase in senescence-associated β-galactosidase activity. In contrast, inhibition of REV3 expression in p53-deficient cells results in growth inhibition and a G(2)/M arrest. A small fraction of the p53-deficient cancer cells can overcome the G(2)/M arrest, which results in mitotic slippage and aneuploidy. Our findings reveal that REV3 depletion per se suppresses growth of cancer cell lines from different origin, whereas control cell lines and a mesothelial primary culture were less affected. Thus, our findings indicate that depletion of REV3 not only can amend cisplatin-based cancer therapy but also can be applied for susceptible cancers as a potential monotherapy.

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Oncology
DDC:610 Medicine & health
Language:English
Date:2011
Deposited On:12 Jan 2012 14:29
Last Modified:08 Dec 2013 16:12
Publisher:Neoplasia Press
ISSN:1476-5586
Publisher DOI:10.1593/neo.11828
Official URL:http://www.neoplasia.com/abstract.php?msid=4534
PubMed ID:22028621
Citations:Web of Science®. Times Cited: 14
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Scopus®. Citation Count: 16

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