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首页> 外文期刊>Biology Open >Excess Polθ functions in response to replicative stress in homologous recombination-proficient cancer cells
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Excess Polθ functions in response to replicative stress in homologous recombination-proficient cancer cells

机译：在同源重组的癌细胞中过度的Polθ响应复制应激

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摘要

DNA polymerase theta (Polθ) is a specialized A-family DNA polymerase that functions in processes such as translesion synthesis (TLS), DNA double-strand break repair and DNA replication timing. Overexpression of?POLQ, the gene encoding Polθ, is a prognostic marker for an adverse outcome in a wide range of human cancers. While increased Polθ dosage was recently suggested to promote survival of homologous recombination (HR)-deficient cancer cells, it remains unclear whether?POLQ?overexpression could be also beneficial to HR-proficient cancer cells. By performing a short interfering (si)RNA screen in which genes encoding druggable proteins were knocked down in Polθ-overexpressing cells as a means to uncover genetic vulnerabilities associated with?POLQ?overexpression, we could not identify genes that were essential for viability in Polθ-overexpressing cells in normal growth conditions. We also showed that, upon external DNA replication stress, Polθ expression promotes cell survival and limits genetic instability. Finally, we report that?POLQ?expression correlates with the expression of a set of HR genes in breast, lung and colorectal cancers. Collectively, our data suggest that Polθ upregulation, besides its importance for survival of HR-deficient cancer cells, may be crucial also for HR-proficient cells to better tolerate DNA replication stress, as part of a global gene deregulation response, including HR genes.
机译：DNA聚合酶theta（Polθ）是一种特殊的A系列DNA聚合酶，可在跨病变合成（TLS），DNA双链断裂修复和DNA复制时间等过程中发挥作用。 βPOLQ（Polθ的编码基因）的过表达是多种人类癌症不良结局的预后标志物。尽管最近提出增加Polθ剂量可促进缺乏同源重组（HR）的癌细胞的存活，但仍不清楚POLQα过表达是否也对HR熟练的癌细胞有益。通过进行简短的干扰（si）RNA筛选，将编码可药用蛋白的基因敲除过表达POL的细胞，以揭示与POLQ过表达相关的遗传脆弱性，我们无法鉴定出对Polθ生存力至关重要的基因在正常生长条件下过度表达细胞。我们还表明，在外部DNA复制压​​力下，Polθ表达可促进细胞存活并限制遗传不稳定性。最后，我们报告说POLQ表达与乳腺癌，肺癌和结直肠癌中一组HR基因的表达相关。总体而言，我们的数据表明，Polθ上调除了对缺损HR的癌细胞的生存至关重要外，对于包括HR基因在内的全球基因失调反应的一部分，对于HR熟练的细胞更好地耐受DNA复制压​​力也可能至关重要。

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