Sir William Dunn School of Pathology, University of Oxford, UK.
FEBS J. 2022 May;289(9):2409-2428. doi: 10.1111/febs.15849. Epub 2021 May 1.
DNA double-strand breaks (DSBs) can result from both exogenous and endogenous sources and are potentially toxic lesions to the human genome. If improperly repaired, DSBs can threaten genome integrity and contribute to premature ageing, neurodegenerative disorders and carcinogenesis. Through decades of work on genome stability, it has become evident that certain regions of the genome are inherently more prone to breakage than others, known as genome instability hotspots. Recent advancements in sequencing-based technologies now enable the profiling of genome-wide distributions of DSBs, also known as breakomes, to systematically map these instability hotspots. Here, we review the application of these technologies and their implications for our current understanding of the genomic regions most likely to drive genome instability. These breakomes ultimately highlight both new and established breakage hotspots including actively transcribed regions, loop boundaries and early-replicating regions of the genome. Further, these breakomes challenge the paradigm that DNA breakage primarily occurs in hard-to-replicate regions. With these advancements, we begin to gain insights into the biological mechanisms both invoking and protecting against genome instability.
DNA 双链断裂（DSBs）可源自内外源，并可能对人类基因组造成潜在的毒性损伤。如果修复不当，DSBs 可能会威胁基因组的完整性，并导致过早衰老、神经退行性疾病和癌症发生。通过对基因组稳定性的数十年研究，很明显某些基因组区域比其他区域更容易发生断裂，这些区域被称为基因组不稳定性热点。基于测序的技术的最新进展现在能够对 DSBs（也称为断裂组）的全基因组分布进行分析，从而系统地绘制这些不稳定性热点图谱。在这里，我们回顾了这些技术的应用及其对我们当前理解最有可能导致基因组不稳定的基因组区域的影响。这些断裂组最终突出了新的和已建立的断裂热点，包括活跃转录区域、环边界和基因组的早期复制区域。此外，这些断裂组挑战了 DNA 断裂主要发生在难以复制区域的范式。随着这些进展，我们开始深入了解引发和防止基因组不稳定性的生物学机制。
