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首页> 外文学位 >The Fanconi anemia pathway and HELQ work alongside dormant replication origins to suppress replication-associated genome instability.
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The Fanconi anemia pathway and HELQ work alongside dormant replication origins to suppress replication-associated genome instability.

机译：Fanconi贫血途径和HELQ与休眠复制起点一起起作用，以抑制复制相关的基因组不稳定。

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摘要

DNA replication is continually impeded by endogenous lesions that cause the stalling of replication forks. If left unchecked, this threatens the integrity of the genome and may be a driver of cancer development. Utilizing the Mcm4chaos3 mouse model, we found that dormant replication origins, which act as backup initiation sites, play a critical role in the recovery of stalled replication forks. A reduced number of dormant origins in these mice led to persistently stalled forks, incomplete replication and the mis-segregation of sister chromatids in mitosis, causing elevated genome instability.;Mcm4chaos3/chaos3 cells also displayed intrinsic activation of the Fanconi anemia (FA) pathway, suggesting that it too plays a functional role in fork progression. Indeed, disruption of FA pathway activation in the Mcm4chaos3/chaos3 background led to an even higher number of persistently stalled forks. Furthermore, we discovered that a lack of dormant origins also leads to delayed replication, as seen by extremely late DNA synthesis. Accordingly, concomitant loss of both mechanisms led to heightened genomic instability, causing mice to either die shortly after birth or exhibit accelerated tumorigenesis.;Finally, we investigated if HELQ is perhaps another FA gene by characterizing the first Helq mutant mouse model (Helqgt). Helqgt/gt cells/mice displayed modest FA-like phenotypes such as interstrand crosslink hypersensitivity and hypogonadism, but not defects in homologous recombination repair. Rather, HELQ was found to work in parallel to the FA protein FANCC to suppress replication-associated genome instability.
机译：DNA复制不断受到内源性病变的阻碍，这些内源性病变会导致复制叉停滞。如果任其发展，这将威胁基因组的完整性，并可能成为癌症发展的驱动力。利用Mcm4chaos3鼠标模型，我们发现休眠复制起点（充当备份启动站点）在停滞的复制叉的恢复中起关键作用。这些小鼠中休眠来源数量的减少导致叉的持续停滞，复制的不完全以及有丝分裂中姐妹染色单体的错误分离，导致基因组不稳定。Mcm4chaos3/ chaos3细胞也显示了Fanconi贫血（FA）途径的内在激活。 ，表明它在分叉进程中也发挥了功能性作用。实际上，在Mcm4chaos3 / chaos3背景中FA途径激活的破坏导致了持续停滞的叉子数量更高。此外，我们发现，缺乏休眠的起源也导致复制延迟，正如DNA合成后期所看到的那样。因此，这两种机制的伴随丧失导致基因组不稳定，导致小鼠要么在出生后不久死亡，要么表现出加速的肿瘤发生。最后，我们通过表征第一个Helq突变小鼠模型（Helqgt）研究了HELQ是否是另一个FA基因。 Helqgt / gt细胞/小鼠显示出适度的FA样表型，例如链间交联超敏和性腺功能减退，但在同源重组修复中没有缺陷。而是，HELQ被发现与FA蛋白FANCC平行发挥作用，以抑制复制相关的基因组不稳定性。

著录项

  • 作者

    Luebben, Spencer William.;

  • 作者单位

    University of Minnesota.;

  • 授予单位 University of Minnesota.;
  • 学科 Biology Genetics.;Biology Molecular.;Biology Cell.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 280 p.
  • 总页数 280
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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