Ran Yehuda, Ido Dromi, Yishai Levin, Thomas Carell, Nicholas Geacintov, Zvi Livneh
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引用次数: 0
Abstract
Hypoxia is common in tumors and is associated with cancer progression and drug resistance, driven, at least in part, by genetic instability. Little is known on how hypoxia affects Translesion DNA Synthesis (TLS), in which error-prone DNA polymerases bypass lesions, thereby maintaining DNA continuity at the price of increased mutations. Here we show that under acute hypoxia, PCNA monoubiquitination, a key step in TLS, and expression of error-prone DNA polymerases increased under regulation of the HIF1α transcription factor. Knocking-down expression of DNA polymerase η, or using PCNA ubiquitination-resistant cells, inhibited genomic DNA replication specifically under hypoxia, and iPOND analysis revealed massive recruitment of TLS DNA polymerases to nascent DNA under hypoxia, uncovering a dramatic involvement of error-prone DNA polymerases in genomic replication. Of note, expression of TLS-polymerases correlates with VEGFA (primary HIF1α target) in a database of renal cell carcinoma, a cancer which accumulates HIF1α. Our results suggest that the tumor microenvironment can lead the cell to forgo, to some extent, the fast and accurate canonical DNA polymerases, for the more flexible and robust, but low-fidelity TLS DNA polymerases. This might endow cancer cells with resilience to overcome replication stress, and mutability to escape the immune system and chemotherapeutic drugs.
缺氧在肿瘤中很常见,与癌症进展和耐药性有关,至少部分原因是遗传不稳定性。人们对缺氧如何影响DNA转座合成(TLS)知之甚少,在TLS中,易出错的DNA聚合酶绕过病变,从而以增加突变为代价维持DNA的连续性。在这里,我们发现在急性缺氧条件下,PCNA单泛素化(TLS的关键步骤)和易错DNA聚合酶的表达在HIF1α转录因子的调控下增加。敲除 DNA 聚合酶 η 的表达,或使用 PCNA 泛素化抗性细胞,可在缺氧条件下抑制基因组 DNA 复制,iPOND 分析显示,在缺氧条件下,TLS DNA 聚合酶被大量招募到新生 DNA 上,从而揭示了易错 DNA 聚合酶在基因组复制中的显著参与。值得注意的是,在肾细胞癌数据库中,TLS聚合酶的表达与血管内皮生长因子(VEGFA)(HIF1α的主要靶标)相关,而肾细胞癌是一种蓄积HIF1α的癌症。我们的研究结果表明,肿瘤微环境会在一定程度上导致细胞放弃快速准确的典型 DNA 聚合酶,转而使用更灵活、更稳健但保真度低的 TLS DNA 聚合酶。这可能会赋予癌细胞克服复制压力的韧性,以及逃避免疫系统和化疗药物的突变性。
期刊介绍:
Oncogene is dedicated to advancing our understanding of cancer processes through the publication of exceptional research. The journal seeks to disseminate work that challenges conventional theories and contributes to establishing new paradigms in the etio-pathogenesis, diagnosis, treatment, or prevention of cancers. Emphasis is placed on research shedding light on processes driving metastatic spread and providing crucial insights into cancer biology beyond existing knowledge.
Areas covered include the cellular and molecular biology of cancer, resistance to cancer therapies, and the development of improved approaches to enhance survival. Oncogene spans the spectrum of cancer biology, from fundamental and theoretical work to translational, applied, and clinical research, including early and late Phase clinical trials, particularly those with biologic and translational endpoints.