Maintenance of genome integrity under physical constraints.
Maintenance of genome integrity under physical constraints.
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DOI：
10.1007/s00412-024-00816-y
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发表时间：
2024-02
期刊：
影响因子：
1.6
通讯作者：
Evi Soutoglou;Philipp Oberdoerffer
中科院分区：
文献类型：
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作者：
Evi Soutoglou;Philipp Oberdoerffer
“跨学科科学”和“打破孤岛”多年来一直是热门词汇。令人鼓舞的是，越来越多的生物学家与其他学科合作或采用其他学科的方法来推动科学进步（Wang et al. 2021）。基因组生物学的研究也不例外。机械力和结构约束可以对核组织、基因组完整性以及最终细胞功能产生深远影响。要理解这种物理约束的生物学影响，不仅需要物理学家的视角，还需要他们的知识和工具。这个特殊的问题将突出作用于和影响细胞核的机械力的范围，从DNA二级结构和三维染色质组织到通过相分离和整个细胞核的物理变形的核区室化。总之，这一系列论文提供了细胞对DNA损伤，DNA复制和核完整性反应的跨学科观点，为我们理解正常生理和疾病中的基因组维护提供了新的视角。我们的收藏从染色质纳米结构的高分辨率视图开始，它是所有DNA交易的基础，并决定了整个核组织。通过对核心组蛋白及其翻译后修饰的单分子FRET分析，Hinde及其同事的原始工作说明了研究表观遗传景观作为完整核结构内空间函数的重要性（Liang et al. 2024）。作者发现，虽然基因激活或抑制性组蛋白标记总体上区分了开放和紧凑的染色质，但在研究活细胞中的染色质结构时，应该考虑单个染色质纤维水平上的显著空间异质性。最后，这项研究打开了大门的染色质亚群，如二价染色质结构域的组合分析。Altmeyer及其同事随后将我们从核小体带到细胞核，并回顾了基因组完整性和机械生物学的交叉点（Spegg和Altmeyer 2023）。在简要讨论了细胞周期调控、DNA复制和细胞对DNA复制应激的反应后，作者探讨了这些过程与驱动DNA修复因子组装的生物物理力之间的复杂联系。以复制蛋白A（RPA）为例，综述强调了修复因子如何形成生物物理缩合物，这种缩合物如何通过DNA损伤诱导的翻译后修饰进行调节，以及这种水平的控制如何直接影响DNA修复过程，如同源性定向的端粒替代延长（ALT）。然后，审查探讨参与核肌动蛋白丝和肌球蛋白在DNA修复和复制应力。作者推测，放线菌球蛋白网络可以作为分子高速公路，将DNA损伤引导到最佳修复环境。有趣的是，病变的移动性似乎
“Interdisciplinary science” and “breaking down silos” have been buzz phrases for many years. It is encouraging to see that indeed more and more biologists have either teamed up with or adopted approaches from other disciplines to advance scientific progress (Wang et al. 2021). The study of genome biology is no exception. Mechanical forces and structural constraints can have profound effects on nuclear organization, genome integrity, and ultimately cell function. To understand the biological impact of such physical constraints requires not only a physicist’s perspective but also their knowledge and tools. This special issue will highlight the range of mechanical forces that act on and affect the nucleus, from DNA secondary structures and three-dimensional chromatin organization to nuclear compartmentalization via phase separation and the physical deformation of entire nuclei. Together, this collection of papers provides a cross-disciplinary view of the cellular response to DNA damage, DNA replication, and nuclear integrity, shedding new light on our understanding of genome maintenance in normal physiology and in disease. Our collection starts with a high-resolution view of the chromatin nanostructure that underlies all DNA transactions and dictates overall nuclear organization. Through single-molecule FRET analyses of core histones and their post-translational modifications, original work by Hinde and colleagues illustrates the importance of studying the epigenetic landscape as a function of space within intact nuclear architecture (Liang et al. 2024). The authors find that, while gene-activating or repressive histone marks do overall distinguish open from compact chromatin, there is significant spatial heterogeneity at the level of single chromatin fibers that should be considered when studying chromatin structure in living cells. Finally, this study opens the door for combinatorial analyses of chromatin sub-populations such as bivalent chromatin domains. Altmeyer and colleagues then take us from nucleosome to nucleus with a review that explores the intersection of genome integrity and mechanobiology (Spegg and Altmeyer 2023). Following a brief discussion of cell cycle regulation, DNA replication, and cellular responses to DNA replication stress, the authors explore the intricate connections between these processes and the biophysical forces that drive DNA repair factor assembly. Using replication protein A (RPA) as an example, the review highlights how repair factors form biophysical condensates, how such condensates can be modulated by DNA damage-induced post-translational modifications, and how this level of control can directly impact DNA repair processes such as the homology-directed Alternative Lengthening of Telomeres (ALT). The review then explores the involvement of nuclear actin filaments and myosin in DNA repair and during replication stress. The authors speculate that actinomyosin networks could serve as molecular highways that direct DNA lesions to optimal repair environments. Intriguingly, lesion mobility appears to