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Proc Natl Acad Sci U S A
2009 Nov 24;10647:19807-12. doi: 10.1073/pnas.0905281106.
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Quaternary structure of the human Cdt1-Geminin complex regulates DNA replication licensing.
De Marco V
,
Gillespie PJ
,
Li A
,
Karantzelis N
,
Christodoulou E
,
Klompmaker R
,
van Gerwen S
,
Fish A
,
Petoukhov MV
,
Iliou MS
,
Lygerou Z
,
Medema RH
,
Blow JJ
,
Svergun DI
,
Taraviras S
,
Perrakis A
.
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All organisms need to ensure that no DNA segments are rereplicated in a single cell cycle. Eukaryotes achieve this through a process called origin licensing, which involves tight spatiotemporal control of the assembly of prereplicative complexes (pre-RCs) onto chromatin. Cdt1 is a key component and crucial regulator of pre-RC assembly. In higher eukaryotes, timely inhibition of Cdt1 by Geminin is essential to prevent DNA rereplication. Here, we address the mechanism of DNA licensing inhibition by Geminin, by combining X-ray crystallography, small-angle X-ray scattering, and functional studies in Xenopus and mammalian cells. Our findings show that the Cdt1:Geminin complex can exist in two distinct forms, a "permissive" heterotrimer and an "inhibitory" heterohexamer. Specific Cdt1 residues, buried in the heterohexamer, are important for licensing. We postulate that the transition between the heterotrimer and the heterohexamer represents a molecular switch between licensing-competent and licensing-defective states.
C303/A5434 Cancer Research UK, C303/A7399 Cancer Research UK, A5434 Cancer Research UK, A7399 Cancer Research UK, CRUK_A5434 Cancer Research UK, CRUK_A7399 Cancer Research UK
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