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.