Human Cdt1 lacking the evolutionarily conserved region that interacts with MCM2-7 is capable of inducing re-replication

28Citations
Citations of this article
47Readers
Mendeley users who have this article in their library.

This article is free to access.

Abstract

Replication initiation must be a carefully regulated process to avoid genomic instability caused by aberrant replication. In eukaryotic cells, distinct steps of protein loading (origin licensing) and replication activation are choreographed such that a cell can replicate only once per cell cycle. The first proteins recruited to the origins form the pre-replication complex. Of these proteins, Cdt1 is of interest, as it is the focus of several pathways to control replication initiation. It is degraded by two different pathways, mediated by the interaction of Cdt1 with proliferating cell nuclear antigen (PCNA) or with cyclin-Cdk2 and inhibited by geminin once cells are in S-phase, presumably to prevent reloading of pre-replication complexes once S-phase has begun. Although the requirement of Cdt1 in loading MCM2-7 is known, the mechanism by which overexpressed Cdt1 stimulates re-replication is unclear. In this study we have designed various mutations in Cdt1 to determine which portion of Cdt1 is important for re-replication, providing insight into possible mechanisms. Surprisingly, we found that mutants of Cdt1 that do not interact with MCM2-7 are able to induce rereplication when overexpressed. The re-replication is not due to titration of geminin from endogenous Cdt1 and is not accompanied by stabilization of endogenous Cdt1. Additionally, the N-terminal one-third of Cdt1 is sufficient to induce re-replication. The N terminus contains the PCNA- and cyclin-interacting motifs, and deletion of both motifs simultaneously in the overexpressed Cdt1 prevents re-replication. These findings suggest that exogenous Cdt1 induces re-replication by de-repressing endogenous Cdt1 through the titration of PCNA and cyclin. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc.

References Powered by Scopus

CLUSTAL W: Improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice

58447Citations
N/AReaders
Get full text

DNA replication in eukaryotic cells

1447Citations
N/AReaders
Get full text

GOR method for predicting protein secondary structure from amino acid sequence

1163Citations
N/AReaders
Get full text

Cited by Powered by Scopus

HBO1 Histone Acetylase Activity Is Essential for DNA Replication Licensing and Inhibited by Geminin

209Citations
N/AReaders
Get full text

Mechanisms for initiating cellular DNA replication

152Citations
N/AReaders
Get full text

Mechanisms and regulation of DNA replication initiation in eukaryotes

131Citations
N/AReaders
Get full text

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Cite

CITATION STYLE

APA

Teer, J. K., & Dutta, A. (2008). Human Cdt1 lacking the evolutionarily conserved region that interacts with MCM2-7 is capable of inducing re-replication. Journal of Biological Chemistry, 283(11), 6817–6825. https://doi.org/10.1074/jbc.M708767200

Readers' Seniority

Tooltip

PhD / Post grad / Masters / Doc 15

43%

Researcher 13

37%

Professor / Associate Prof. 7

20%

Readers' Discipline

Tooltip

Agricultural and Biological Sciences 23

59%

Biochemistry, Genetics and Molecular Bi... 11

28%

Medicine and Dentistry 4

10%

Pharmacology, Toxicology and Pharmaceut... 1

3%

Save time finding and organizing research with Mendeley

Sign up for free