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Genes 2015, 6(2), 252-266; doi:10.3390/genes6020252

An Inactive Geminin Mutant That Binds Cdt1

1
Department of Medicine, Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University Chicago, IL 60610, USA
2
Epigenetics and Cell Fate, Sorbonne Paris Cité, University Paris Diderot, UMR 7216 CNRS, Paris 75013, France
3
George Wahlen Veterans Affairs Medical Center, Room 2E 24, 500 Foothill Drive, Salt Lake City, UT 84103, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Peter Frank
Received: 31 March 2015 / Revised: 24 April 2015 / Accepted: 28 April 2015 / Published: 15 May 2015
(This article belongs to the Special Issue DNA Replication)
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Abstract

The initiation of DNA replication is tightly regulated in order to ensure that the genome duplicates only once per cell cycle. In vertebrate cells, the unstable regulatory protein Geminin prevents a second round of DNA replication by inhibiting the essential replication factor Cdt1. Cdt1 recruits mini-chromosome maintenance complex (MCM2-7), the replication helicase, into the pre-replication complex (pre-RC) at origins of DNA replication. The mechanism by which Geminin inhibits MCM2-7 loading by Cdt1 is incompletely understood. The conventional model is that Geminin sterically hinders a direct physical interaction between Cdt1 and MCM2-7. Here, we describe an inactive missense mutant of Geminin, GemininAWA, which binds to Cdt1 with normal affinity yet is completely inactive as a replication inhibitor even when added in vast excess. In fact, GemininAWA can compete with GemininWT for binding to Cdt1 and prevent it from inhibiting DNA replication. GemininAWA does not inhibit the loading of MCM2-7 onto DNA in vivo, and in the presence of GemininAWA, nuclear DNA is massively over-replicated within a single S phase. We conclude that Geminin does not inhibit MCM loading by simple steric interference with a Cdt1-MCM2-7 interaction but instead works by a non-steric mechanism, possibly by inhibiting the histone acetyltransferase HBO1. View Full-Text
Keywords: DNA replication; pre-replication complex; Cdt1; geminin; HBO1 DNA replication; pre-replication complex; Cdt1; geminin; HBO1
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Suchyta, M.; Miotto, B.; McGarry, T.J. An Inactive Geminin Mutant That Binds Cdt1. Genes 2015, 6, 252-266.

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