Zribi Sara, Giannitelli Gladio Joel, Bernardini Laura, Censi Federica, Camerini Serena, Bertuccini Lucia, Iosi Francesca, Giannella Emilia, Sanchez Massimo, Consoli Elisa, Casagrande Andrea, Cenci Alessandra, Floridia Giovanna, Novelli Antonio, Giuliani Alessandro, Costanzo Vincenzo, Crescenzi Marco, Pajalunga Deborah
Core Facilities, Italian National Institute of Health, Rome, Italy.
Medical Genetics Division, Casa Sollievo della Sofferenza Foundation, San Giovanni Rotondo, FG, Rome, Italy.
EMBO Rep. 2025 Aug 26. doi: 10.1038/s44319-025-00554-x.
Terminal cell differentiation is often associated with permanent withdrawal from proliferation, termed the postmitotic state. Though widespread among vertebrates and determinant for their biology, the molecular underpinnings of this state are poorly understood. Postmitotic skeletal muscle myotubes can be induced to reenter the cell cycle; however, they generally die as a result of their inability to complete DNA replication. Here, we explore the causes of such incompetence. Genomic hybridization of newly synthesized DNA shows that the replicative failure does not concern specific genomic regions, but can stochastically affect any of them. Myoblast and myotube nuclei are incubated in replicative Xenopus egg extract, which provides a full DNA replication machinery. While myoblast nuclei attain complete DNA replication, those from myotubes, even in these conditions, duplicate less than half of their genomes, strongly indicating that the structure of myotube chromatin obstructs DNA replication. Furthermore, disassembling and disorganizing chromatin with a strong salt treatment does not modify the replicative differences between the two types of nuclei, suggesting that they are rooted in the core structure of chromatin.
终末细胞分化通常与永久性退出增殖相关，即所谓的有丝分裂后状态。尽管这种状态在脊椎动物中广泛存在且对其生物学特性起决定性作用，但其分子基础仍知之甚少。有丝分裂后的骨骼肌肌管可被诱导重新进入细胞周期；然而，它们通常因无法完成DNA复制而死亡。在此，我们探究这种无能的原因。新合成DNA的基因组杂交表明，复制失败并非涉及特定的基因组区域，而是可能随机影响其中任何一个区域。将成肌细胞和成肌管细胞核置于具有复制能力的非洲爪蟾卵提取物中，该提取物提供完整的DNA复制机制。虽然成肌细胞核能够完成DNA复制，但即使在这些条件下，来自肌管的细胞核复制的基因组不到其一半，这强烈表明肌管染色质的结构阻碍了DNA复制。此外，用强盐处理拆解和打乱染色质并不会改变两种类型细胞核之间的复制差异，这表明它们源于染色质的核心结构。
