Breaking the paradigm: early insights from mammalian DNA breakomes.
Breaking the paradigm: early insights from mammalian DNA breakomes.
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DOI：
10.1111/febs.15849
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发表时间：
2022-05
期刊：
影响因子：
5.4
通讯作者：
Esashi, Fumiko
中科院分区：
文献类型：
--
作者：
Saayman, Xanita;Esashi, Fumiko
DNA双链断裂(DSB)可由外源性和内源性两种来源引起，对人类基因组具有潜在的毒性损伤。如果修复不当，DSB可能威胁到基因组的完整性，并导致过早衰老、神经退行性疾病和癌症发生。通过几十年来对基因组稳定性的研究，已经变得明显的是，基因组的某些区域天生比其他区域更容易断裂，这被称为基因组不稳定热点。基于测序技术的最新进展现在能够对DSB的全基因组分布进行剖析，也称为断体，以系统地定位这些不稳定的热点。在这里，我们回顾了这些技术的应用及其对我们目前对最可能驱动基因组不稳定的基因组区域的理解的影响。这些断体最终突出了新的和已经建立的断点热点，包括基因组的活跃转录区域、环边界和早期复制区。此外，这些断裂体挑战了DNA断裂主要发生在难以复制的区域的范式。随着这些进展，我们开始深入了解引发和保护基因组不稳定的生物学机制。基于测序技术的最新进展允许检测全基因组范围的DNA断裂，提供了在各种实验条件下全基因组断裂易感性的无偏见快照。将这些数据与基因组和表观基因组信息配对，研究人员开始深入了解引发和防止DNA断裂的分子机制。在这里，我们回顾了这些技术的应用及其对我们目前对基因组不稳定驱动因素的理解的影响。
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. Recent advancements in sequencing‐based technologies allow the detection of DNA breaks genome‐wide, providing an unbiased snapshot of genome‐wide break susceptibility in various experimental conditions. Pairing these data with genomic and epigenomic information, researchers are beginning to gain insight into the molecular mechanisms both provoking and protecting against DNA breaks. Here, we review the application of these technologies and their implications for our current understanding of the drivers of genome instability.
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