Department of Environment and Health, Section of Mechanisms Biomarkers and Models, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
Int J Mol Sci. 2022 Jan 28;23(3):1547. doi: 10.3390/ijms23031547.
Maintenance of genome stability is crucial for cell survival and relies on accurate DNA replication. However, replication fork progression is under constant attack from different exogenous and endogenous factors that can give rise to replication stress, a source of genomic instability and a notable hallmark of pre-cancerous and cancerous cells. Notably, one of the major natural threats for DNA replication is transcription. Encounters or conflicts between replication and transcription are unavoidable, as they compete for the same DNA template, so that collisions occur quite frequently. The main harmful transcription-associated structures are R-loops. These are DNA structures consisting of a DNA-RNA hybrid and a displaced single-stranded DNA, which play important physiological roles. However, if their homeostasis is altered, they become a potent source of replication stress and genome instability giving rise to several human diseases, including cancer. To combat the deleterious consequences of pathological R-loop persistence, cells have evolved multiple mechanisms, and an ever growing number of replication fork protection factors have been implicated in preventing/removing these harmful structures; however, many others are perhaps still unknown. In this review, we report the current knowledge on how aberrant R-loops affect genome integrity and how they are handled, and we discuss our recent findings on the role played by two fork protection factors, the Werner syndrome protein (WRN) and the Werner helicase-interacting protein 1 (WRNIP1) in response to R-loop-induced genome instability.
维持基因组稳定性对于细胞存活至关重要，这依赖于精确的 DNA 复制。然而，复制叉的推进不断受到来自不同外源性和内源性因素的攻击，这些因素会导致复制应激，这是基因组不稳定性的一个来源，也是癌前和癌细胞的一个显著特征。值得注意的是，DNA 复制的一个主要自然威胁是转录。复制和转录之间的相遇或冲突是不可避免的，因为它们争夺同一个 DNA 模板，因此碰撞经常发生。主要的有害转录相关结构是 R 环。这些是由 DNA-RNA 杂交体和移位的单链 DNA 组成的 DNA 结构，它们在生理上起着重要作用。然而，如果它们的内稳态发生改变，它们就会成为复制应激和基因组不稳定性的一个潜在来源，导致包括癌症在内的多种人类疾病。为了对抗病理 R 环持续存在的有害后果，细胞已经进化出多种机制，越来越多的复制叉保护因子被认为可以预防/去除这些有害结构；然而，许多其他因子可能仍然未知。在这篇综述中，我们报告了关于异常 R 环如何影响基因组完整性以及它们是如何被处理的最新知识，并讨论了我们最近关于两个叉保护因子（WRN 蛋白和 WRN 解旋酶相互作用蛋白 1）在应对 R 环诱导的基因组不稳定性方面所起作用的发现。
