QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

First published online 2 November 2004
doi: 10.1242/jcs.01503

This Article Figures Only Full Text Full Text (PDF) All Versions of this Article: jcs.01503v1 117/24/5875    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Eward, K. L. Articles by Williams, G. H. Search for Related Content PubMed PubMed Citation Articles by Eward, K. L. Articles by Williams, G. H. Social Bookmarking                         What's this?

DNA replication licensing in somatic and germ cells

Kathryn Leigh Eward^1,*, Ellen C. Obermann^2,*, S. Shreeram³, Marco Loddo², Thomas Fanshawe⁴, Craig Williams¹, Hyo-Il Jung¹, A. Toby Prevost⁵, J. Julian Blow³, Kai Stoeber^1,2, and Gareth H. Williams^1,2

¹ Wolfson Institute for Biomedical Research, University College London, The Cruciform Building, Gower Street, London, WC1E 6BT, UK
² Department of Histopathology, University College London, Rockefeller Building, University Street, London, WC1E 6JJ, UK
³ Welcome Trust Biocentre, University of Dundee, Dow Street, Dundee, DD1 5EH, UK
⁴ Centre for Applied Medical Statistics and General Practice and Primary Care Research Unit, Department of Public Health and Primary Care, University of Cambridge, Forvie Site, Robinson Way, Cambridge, CB2 2SR, UK
⁵ Medical Research Council Biostatistics Unit, Institute of Public Health, Forvie Site, Robinson Way, Cambridge, CB2 2SR, UK

Author for correspondence (e-mail: k.stoeber{at}ucl.ac.uk)

Accepted 19 August 2004

The DNA replication (or origin) licensing system ensures precise duplication of the genome in each cell cycle and is a powerful regulator of cell proliferation in metazoa. Studies in yeast, Drosophila melanogaster and Xenopus laevis have characterised the molecular machinery that constitutes the licensing system, but it remains to be determined how this important evolutionary conserved pathway is regulated in Homo sapiens. We have investigated regulation of the origin licensing factors Cdc6, Cdt1, Mcm2 and Geminin in human somatic and germ cells. Cdc6 and Cdt1 play an essential role in DNA replication initiation by loading the Mcm2-7 complex, which is required for unwinding the DNA helix, onto chromosomal origins. Geminin is a repressor of origin licensing that blocks Mcm2-7 loading onto origins. Our studies demonstrate that Cdc6, Cdt1 and Mcm2 play a central role in coordinating growth during the proliferation-differentiation switch in somatic self-renewing systems and that Cdc6 expression is rate-limiting for acquisition of replication competence in primary oocytes. In striking contrast, we show that proliferation control during male gametogenesis is not linked to Cdc6 or Mcm2, but appears to be coordinated by the negative regulator Geminin with Cdt1 becoming rate-limiting in late prophase. Our data demonstrate a striking sexual dimorphism in the mechanisms repressing origin licensing and preventing untimely DNA synthesis during meiosis I, implicating a pivotal role for Geminin in maintaining integrity of the male germline genome.

Key words: Ki67, Cdc6, Cdt1, MCM, Geminin, DNA replication licensing, Oogenesis, Spermatogenesis, Gametogenesis

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				A. A. Kulkarni, S. R. Kingsbury, S. Tudzarova, H.-K. Hong, M. Loddo, M. Rashid, S. Rodriguez-Acebes, A. T. Prevost, J. A. Ledermann, K. Stoeber, et al. Cdc7 Kinase Is a Predictor of Survival and a Novel Therapeutic Target in Epithelial Ovarian Carcinoma Clin. Cancer Res., April 1, 2009; 15(7): 2417 - 2425. [Abstract] [Full Text] [PDF]

				S. V. Srinivasan, C. N. Mayhew, S. Schwemberger, W. Zagorski, and E. S. Knudsen RB Loss Promotes Aberrant Ploidy by Deregulating Levels and Activity of DNA Replication Factors J. Biol. Chem., August 17, 2007; 282(33): 23867 - 23877. [Abstract] [Full Text] [PDF]

				P. E. Cohen, S. E. Pollack, and J. W. Pollard Genetic Analysis of Chromosome Pairing, Recombination, and Cell Cycle Control during First Meiotic Prophase in Mammals Endocr. Rev., June 1, 2006; 27(4): 398 - 426. [Abstract] [Full Text] [PDF]