ABSTRACT Mammalian nuclei are equipped with a framework of intermediate filaments that function as a karyoskeleton. This nuclear scaffold, formed primarily by lamins (A-type and B-type), maintains the spatial and functional organization of the genome and of sub-nuclear compartments. Over the past decade, a body of evidence has highlighted the significance of these structural nuclear proteins in the maintenance of nuclear architecture and mechanical stability, as well as genome function and integrity. The importance of these structures is now unquestioned given the wide range of degenerative diseases that stem from LMNA gene mutations, including muscular dystrophy disorders, peripheral neuropathies, lipodystrophies, and premature aging syndromes. Here, we review our knowledge about how alterations in nuclear lamins, either by mutation or reduced expression, impact cellular mechanisms that maintain genome integrity. Despite the fact that DNA replication is the major source of DNA damage and genomic instability in dividing cells, how alterations in lamins function impact replication remains minimally explored. We summarize recent studies showing that lamins play a role in DNA replication, and that the DNA damage that accumulates upon lamins dysfunction is elicited in part by deprotection of replication forks. We also discuss the emerging model that DNA damage and replication stress are “sensed” at the cytoplasm by proteins that normally survey this space in search of foreign nucleic acids. In turn, these cytosolic sensors activate innate immune responses, which are materializing as important players in aging and cancer, as well as in the response to cancer immunotherapy.

中文翻译：

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椎板病基因组不稳定性的原因和后果：复制应激和干扰素反应

摘要哺乳动物的细胞核配备了中间细丝的框架，起到核骨架的作用。这种核支架主要由核纤层蛋白（A 型和 B 型）形成，维持基因组和亚核区室的空间和功能组织。在过去十年中，大量证据强调了这些结构核蛋白在维持核结构和机械稳定性以及基因组功能和完整性方面的重要性。鉴于源自 LMNA 基因突变的广泛退行性疾病，包括肌肉萎缩症、周围神经病、脂肪营养不良和过早衰老综合征，这些结构的重要性现在是毋庸置疑的。在这里，我们回顾了我们关于核纤层蛋白如何改变的知识，通过突变或减少表达，影响维持基因组完整性的细胞机制。尽管 DNA 复制是分裂细胞中 DNA 损伤和基因组不稳定性的主要来源，但对核纤层蛋白功能的改变如何影响复制的研究仍然很少。我们总结了最近的研究，表明核纤层蛋白在 DNA 复制中发挥作用，并且在核纤层蛋白功能障碍时积累的 DNA 损伤部分是由复制叉的脱保护引起的。我们还讨论了一种新兴模型，即 DNA 损伤和复制压力在细胞质中被蛋白质“感知”，这些蛋白质通常会在这个空间中寻找外来核酸。反过来，这些细胞质传感器激活先天免疫反应，这些反应正在成为衰老和癌症的重要参与者，