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. 2015 Aug;37(8):856-61.
doi: 10.1002/bies.201500021. Epub 2015 Jun 9.

Understanding Replication Fork Progression, Stability, and Chromosome Fragility by Exploiting the Suppressor of Underreplication Protein

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Free PMC article

Understanding Replication Fork Progression, Stability, and Chromosome Fragility by Exploiting the Suppressor of Underreplication Protein

Jared T Nordman et al. Bioessays. .
Free PMC article

Abstract

There are many layers of regulation governing DNA replication to ensure that genetic information is accurately transmitted from mother cell to daughter cell. While much of the control occurs at the level of origin selection and firing, less is known about how replication fork progression is controlled throughout the genome. In Drosophila polytene cells, specific regions of the genome become repressed for DNA replication, resulting in underreplication and decreased copy number. Importantly, underreplicated domains share properties with common fragile sites. The Suppressor of Underreplication protein SUUR is essential for this repression. Recent work established that SUUR functions by directly inhibiting replication fork progression, raising several interesting questions as to how replication fork progression and stability can be modulated within targeted regions of the genome. Here we discuss potential mechanisms by which replication fork inhibition can be achieved and the consequences this has on genome stability and copy number control.

Keywords: DNA replication; Drosophila; common fragile sites; endocycle; genome stability; polyploidy; underreplication.

Figures

Figure 1
Figure 1
Conservation of SUUR. A: Conservation of SUUR across twelve Drosophila species. Alignments and conservation scores were generated with UCSC genome browser. B: Conservation of the Walker A and B regions from multiple SNF2 domain-containing proteins in Drosophila. Asterisks mark the sites of key residues involved in ATP binding and hydrolysis that are not conserved in SUUR. Alignments were generated using ClustalW and BoxShade.
Figure 2
Figure 2
Potential models by which SUUR could inhibit active replication forks. Depicted is a model in which SUUR becomes recruited to replication forks late in S phase. Once at a replication fork, SUUR could prevent the decondensation of highly condensed regions of chromatin (e.g. heterochromatin) through competition with a chromatin remodeling factor. Also, SUUR could directly inhibit a key activity associated with replication fork progression, such as helicase activity. It is important to note that these two models of SUUR function are not mutually exclusive.

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