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
Whitehead Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
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.
Cell Rep. 2014 Nov 6;9(3):841-9. doi: 10.1016/j.celrep.2014.10.005. Epub 2014 Oct 30.
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.
对DNA复制进行适当控制对于确保遗传物质的准确传递以及防止可能推动癌症进展和发育障碍的染色体畸变至关重要。DNA复制主要在起始水平受到调控，并处于严格的细胞周期调控之下。重要的是，DNA复制受到发育信号的高度影响。在果蝇中，基因组的特定区域在分化过程中通过含SNF2结构域的蛋白SUUR以未知机制被抑制进行DNA复制。我们证明，SUUR被招募到活跃的复制叉，并通过直接抑制复制叉进展而非作为复制叉屏障来介导DNA复制的抑制。对与SUUR相关蛋白的质谱鉴定确定了复制解旋酶成员CDC45为与SUUR相关的蛋白，支持了SUUR直接在复制叉发挥作用的观点。我们的结果表明，真核生物DNA拷贝数的控制可通过抑制复制叉进展来实现。
