title: DNA copy-number control through inhibition of replication fork progression.
abstract: 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.
authors.affiliation: Whitehead Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Jared T
authors.initials: JT
authors.lastname: Nordman
authors.affiliation: Erasmus University Medical Centre, P.O. Box 1738, 3000 DR Rotterdam, the Netherlands; Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Lavrentyev Avenue 10, Novosibirsk 630090, Russia.
authors.forename: Elena N
authors.initials: EN
authors.lastname: Kozhevnikova
authors.affiliation: Erasmus University Medical Centre, P.O. Box 1738, 3000 DR Rotterdam, the Netherlands.
authors.forename: C Peter
authors.initials: CP
authors.lastname: Verrijzer
authors.affiliation: Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; Institute of Molecular and Cellular Biology, Siberian Branch of Russian Academy of Sciences, Lavrentyev Avenue 8/2, Novosibirsk 630090, Russia; Novosibirsk State University, Pirogova St. 2, Novosibirsk 630090, Russia.
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Pindyurin
authors.affiliation: Institute of Molecular and Cellular Biology, Siberian Branch of Russian Academy of Sciences, Lavrentyev Avenue 8/2, Novosibirsk 630090, Russia.
authors.forename: Evgeniya N
authors.initials: EN
authors.lastname: Andreyeva
authors.affiliation: Institute of Molecular and Cellular Biology, Siberian Branch of Russian Academy of Sciences, Lavrentyev Avenue 8/2, Novosibirsk 630090, Russia.
authors.forename: Victor V
authors.initials: VV
authors.lastname: Shloma
authors.affiliation: Institute of Molecular and Cellular Biology, Siberian Branch of Russian Academy of Sciences, Lavrentyev Avenue 8/2, Novosibirsk 630090, Russia; Novosibirsk State University, Pirogova St. 2, Novosibirsk 630090, Russia.
authors.forename: Igor F
authors.initials: IF
authors.lastname: Zhimulev
authors.affiliation: Whitehead Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Electronic address: weaver@wi.mit.edu.
authors.forename: Terry L
authors.initials: TL
authors.lastname: Orr-Weaver
mesh_terms: D000818:Animals; D056915:DNA Copy Number Variations / Q000235:genetics*; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D029721:Drosophila Proteins / Q000737:chemistry / Q000378:metabolism; D004331:Drosophila melanogaster / Q000378:metabolism*; D018628:Gene Dosage; D013058:Mass Spectrometry; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C464850:SuUR protein, Drosophila