DNA Copy-Number Control through Inhibition of Replication Fork Progression

• Published in: Cell reports (Cambridge) Vol. 9; no. 3; pp. 841 - 849
• Main Authors: Nordman, Jared T., Kozhevnikova, Elena N., Verrijzer, C. Peter, Pindyurin, Alexey V., Andreyeva, Evgeniya N., Shloma, Victor V., Zhimulev, Igor F., Orr-Weaver, Terry L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.11.2014; Elsevier
• Subjects: Animals; DNA Copy Number Variations - genetics; DNA Replication; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - metabolism; Drosophila melanogaster - metabolism; Drosophila Proteins - chemistry; Drosophila Proteins - metabolism; Gene Dosage; Mass Spectrometry; Protein Binding; Protein Structure, Tertiary; Protein Transport
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2014.10.005

Proper control of DNA replication is essential to ensure faithful transmission of genetic material and prevent chromosomal aberrations that can drive cancer progression and developmental disorders. DNA replication is regulated primarily at the level of initiation and is under strict cell-cycle regulation. Importantly, DNA replication is highly influenced by developmental cues. In Drosophila, specific regions of the genome are repressed for DNA replication during differentiation by the SNF2 domain-containing protein SUUR through an unknown mechanism. We demonstrate that SUUR is recruited to active replication forks and mediates the repression of DNA replication by directly inhibiting replication fork progression instead of functioning as a replication fork barrier. Mass spectrometry identification of SUUR-associated proteins identified the replicative helicase member CDC45 as a SUUR-associated protein, supporting a role for SUUR directly at replication forks. Our results reveal that control of eukaryotic DNA copy number can occur through the inhibition of replication fork progression. [Display omitted] •Replication fork progression is subject to developmental control•The SUUR chromatin protein localizes to active replication forks•SUUR inhibits replication fork progression in specific developmental contexts•DNA copy number can be controlled through modulation of replication fork progression Proper genome duplication relies on both initiation and elongation phases of DNA replication, and regulation of DNA replication is thought to occur predominantly at the level of initiation. By studying developmentally programmed repression of DNA replication in Drosophila, Nordman et al. now find that a metazoan protein can control DNA replication and copy number through direct inhibition of replication fork progression.