Morgunova Valeriya V, Sokolova Olesya A, Sizova Tatyana V, Malaev Leonid G, Babaev Dmitry S, Kwon Dmitry A, Kalmykova Alla I
Institute of Molecular Genetics of National Research Centre "Kurchatov Institute", Moscow, 123182, Russia.
Faculty of Biotechnology, Lomonosov Moscow State University, Moscow, 119991, Russia.
Biochemistry (Mosc). 2022 Dec;87(12):1600-1610. doi: 10.1134/S000629792212015X.
Chromatin spatial organization in the nucleus is essential for the genome functioning and regulation of gene activity. The nuclear lamina and lamina-associated proteins, lamins, play a key role in this process. Lamin dysfunction leads to the decompaction and transcriptional activation of heterochromatin, which is associated with the premature aging syndrome. In many cell types, telomeres are located at the nuclear periphery, where their replication and stability are ensured by the nuclear lamina. Moreover, diseases associated with defects in lamins and telomeres have similar manifestations and resemble physiological aging. Understanding molecular changes associated with aging at the organismal level is especially important. In this study, we compared the effects caused by the mutation in lamin B and physiological aging in the germline of the model organism Drosophila melanogaster. We have shown that the impaired localization of lamin B leads to the heterochromatin decompaction and transcriptional activation of some transposable elements and telomeric repeats. Both DNA damage and activation of homologous recombination in the telomeres were observed in the germ cells of lamin B mutants. The instability of repeat-enriched heterochromatin can be directly related to the genome destabilization, germ cell death, and sterility observed in lamin B mutants. Similar processes were observed in Drosophila germline in the course of physiological aging, which indicates a close link between the maintenance of the heterochromatin stability at the nuclear periphery and mechanisms of aging.
细胞核中的染色质空间组织对于基因组功能和基因活性调控至关重要。核纤层及与核纤层相关的蛋白质（核纤层蛋白）在这一过程中发挥关键作用。核纤层蛋白功能障碍会导致异染色质解聚和转录激活，这与早衰综合征相关。在许多细胞类型中，端粒位于核周边，其复制和稳定性由核纤层确保。此外，与核纤层蛋白和端粒缺陷相关的疾病有相似表现，且类似于生理性衰老。了解生物体水平上与衰老相关的分子变化尤为重要。在本研究中，我们比较了模型生物黑腹果蝇生殖系中核纤层蛋白B突变和生理性衰老所造成的影响。我们发现，核纤层蛋白B定位受损会导致异染色质解聚以及一些转座元件和端粒重复序列的转录激活。在核纤层蛋白B突变体的生殖细胞中观察到了DNA损伤和端粒中同源重组的激活。富含重复序列的异染色质的不稳定性可能直接与核纤层蛋白B突变体中观察到的基因组不稳定、生殖细胞死亡和不育相关。在生理性衰老过程中，黑腹果蝇生殖系中也观察到了类似过程，这表明核周边异染色质稳定性的维持与衰老机制之间存在密切联系。
