Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2009 Jun 1;14(13):5013-30.
doi: 10.2741/3584.

Replication licensing and the DNA damage checkpoint

Jeanette Gowen Cook  1
Affiliations
Review

Replication licensing and the DNA damage checkpoint

Jeanette Gowen Cook. Front Biosci (Landmark Ed). .

Abstract

Accurate and timely duplication of chromosomal DNA requires that replication be coordinated with processes that ensure genome integrity. Significant advances in determining how the earliest steps in DNA replication are affected by DNA damage have highlighted some of the mechanisms to establish that coordination. Recent insights have expanded the relationship between the ATM and ATR-dependent checkpoint pathways and the proteins that bind and function at replication origins. These findings suggest that checkpoints and replication are more intimately associated than previously appreciated, even in the absence of exogenous DNA damage. This review summarizes some of these developments.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Replication licensing is restricted to G1. Pre-replication complexes (preRC) are assembled at origins during G1 by the loading of MCM complexes by ORC, Cdc6, and Cdt1. Origin firing requires loading of Cdc45 and GINS (not shown) which is induced by the action of Cdk2 and Cdc7 in S phase. After the G1/S transition Cdk2 (and Cdk1) plus geminin inhibition of Cdt1 block any new MCM chromatin loading in order to prevent rereplication.
Figure 2
Figure 2
DNA damage induces intracellular signaling cascades that block DNA replication and cell cycle progression. Two parallel branches, the ATR-Chk1 and ATM-Chk2 pathways are activated by different forms of damage. Cdk activity is inhibited by degradation/inhibition of Cdc25 phosphatases and by the p53-dependent induction of the p21 Cdk inhibitor. Cdk-independent events also block origin firing through inhibition of Cdk and Cdc7 kinase activity. The Tlk1 kinase which promotes Asf1-dependent chromatin assembly is also inactivated in response to DNA damage.
Figure 3
Figure 3
DNA damage regulates both origin licensing and origin firing. DNA damage induces the phosphorylation of MCM and ORC subunits, while stimulating the ubiquitination and degradation of Cdt1 and Cdc6. The DNA damage-activated checkpoint also blocks Cdc45 loading at origins to prevent replication initiation.
See this image and copyright information in PMC

References

    1. Diffley JF. Regulation of early events in chromosome replication. Curr Biol. 2004;14(18):R778–R786. - PubMed
    1. Sclafani RA, Holzen TM. Cell Cycle Regulation of DNA Replication. Annu Rev Genet. 2007 - PMC - PubMed
    1. Prasanth SG, Mendez J, Prasanth KV, Stillman B. Dynamics of pre-replication complex proteins during the cell division cycle. Philos Trans R Soc Lond B Biol Sci. 2004;359(1441):7–16. - PMC - PubMed
    1. Blow JJ, Dutta A. Preventing re-replication of chromosomal DNA. Nat Rev Mol Cell Biol. 2005;6(6):476–486. - PMC - PubMed
    1. Machida YJ, Hamlin JL, Dutta A. Right Place, Right Time, and Only Once: Replication Initiation in Metazoans. Cell. 2005;123(1):13–24. - PubMed

Publication types