Effect of minichromosome maintenance protein 2 deficiency on the locations of DNA replication origins.
Effect of minichromosome maintenance protein 2 deficiency on the locations of DNA replication origins.
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DOI：
10.1101/gr.176099.114
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发表时间：
2015-04
期刊：
影响因子：
7
通讯作者：
Pruitt SC
中科院分区：
文献类型：
--
作者：
Kunnev D;Freeland A;Qin M;Leach RW;Wang J;Shenoy RM;Pruitt SC
微小染色体维持（MCM）蛋白在G1期装载到染色质上，并定义DNA复制起始的潜在位置。在小鼠模型中，MCM蛋白缺乏导致基因组不稳定和高癌症发生率。在这里，我们开发了一种新生链捕获和释放的方法，并表明MCM 2缺陷减少了基因组中基因丰富区域的DNA复制起始。DNA结构特性与复制起点相关的序列基序和优先受MCM 2缺陷影响的位置相关。新生链密度降低与MCM 2缺陷小鼠肿瘤中复发性局灶性CNVs的位点相关，这与DNA复制起始位点降低和遗传损伤之间的直接关系一致。根据类型的不同，10%至90%的人类肿瘤携带一个或多个MCM 2 -7基因的杂合丢失或突变，这预计会损害DNA复制起点许可，并导致基因组损伤率升高。
Minichromosome maintenance (MCM) proteins are loaded onto chromatin during G1-phase and define potential locations of DNA replication initiation. MCM protein deficiency results in genome instability and high rates of cancer in mouse models. Here we develop a method of nascent strand capture and release and show that MCM2 deficiency reduces DNA replication initiation in gene-rich regions of the genome. DNA structural properties are shown to correlate with sequence motifs associated with replication origins and with locations that are preferentially affected by MCM2 deficiency. Reduced nascent strand density correlates with sites of recurrent focal CNVs in tumors arising in MCM2-deficient mice, consistent with a direct relationship between sites of reduced DNA replication initiation and genetic damage. Between 10% and 90% of human tumors, depending on type, carry heterozygous loss or mutation of one or more MCM2-7 genes, which is expected to compromise DNA replication origin licensing and result in elevated rates of genome damage at a subset of gene-rich locations.
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影响因子：
64.5
作者：
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通讯作者：
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