Cell type-specific responses of human cells to inhibition of replication licensing

Shreeram, S., Sparks, Alison, Lane, David P. and Blow, J. Julian (2002) Cell type-specific responses of human cells to inhibition of replication licensing. Oncogene, 21 (43). pp. 6624-6632. ISSN 0950-9232

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Abstract

Replication origins are 'licensed' for a single initiation event by loading Mcm2-7 complexes during late mitosis and G1. Licensing is blocked at other cell cycle stages by the activity of cyclin-dependent kinases and a small protein called geminin. Here, we describe the effects of over-expressing a non-degradable form of geminin in various cell lines. Geminin expression reduced the quantity of Mcm2 bound to chromatin and blocked cell proliferation. U2OS (p53+/Rb+) cells showed an early S phase arrest with high cyclin E and undetectable cyclin A levels, consistent with the activation of an intra-S checkpoint. Saos2 (p53-/Rb-) cells showed an accumulation of cells in late S and G2/M with approximately normal levels of cyclin A, consistent with loss of this intra-S phase checkpoint. Geminin also induced apoptosis in both these cell lines. In contrast, IMR90 primary fibroblasts over-expressing geminin arrested in G1 with reduced cyclin E levels and no detectable apoptosis. A 'licensing checkpoint' may therefore act in primary cells to prevent passage into S phase in the absence of sufficient origin licensing. These results suggest that inhibition of the licensing system may cause cancer-specific cell killing and therefore represent a novel anti-cancer target.

Item Type: Article
Additional Information: Funding information: This work was supported by a British Commonwealth scholarship to S. Shreeram and Cancer Research UK grant SP2385/0101. Other information: This work is the subject of UK patent application 0209508.1.
Uncontrolled Keywords: sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
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Depositing User: LivePure Connector
Date Deposited: 10 Jun 2024 16:30
Last Modified: 17 Jun 2024 00:18
URI: https://ueaeprints.uea.ac.uk/id/eprint/95519
DOI: 10.1038/sj.onc.1205910

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