Molecular mechanisms protecting centromeres from self-sabotage and implications for cancer therapy.
Molecular mechanisms protecting centromeres from self-sabotage and implications for cancer therapy.
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着丝粒在细胞分裂过程中通过调节姐妹染色单体的凝聚和分离在DNA分离中起着至关重要的作用。着丝粒功能障碍、断裂或受损的着丝粒完整性可产生非整倍性和染色体不稳定性，这是与癌症起始和进展相关的细胞特征。因此，保持着丝粒的完整性对基因组的稳定性至关重要。然而，着丝粒本身容易发生DNA断裂，可能是由于其固有的脆弱性。着丝粒是由高度重复的DNA序列和二级结构组成的复杂基因组位点，需要着丝粒相关蛋白网络的募集和稳态。参与保存着丝粒固有结构和对着丝粒损伤作出反应的分子机制尚未完全理解，仍然是正在进行的研究的主题。在这篇文章中，我们提供了一个审查目前已知的因素，有助于着丝粒功能障碍和分子机制，减轻着丝粒损伤对基因组稳定性的影响。最后，我们讨论了潜在的治疗策略，可能会产生更深入的了解机制，保持着丝粒的完整性。着丝粒由于其重复序列和二级结构而本质上是脆弱的。越来越多的证据表明存在特定的机制来防止着丝粒相关的基因组不稳定性。
Centromeres play a crucial role in DNA segregation by mediating the cohesion and separation of sister chromatids during cell division. Centromere dysfunction, breakage or compromised centromeric integrity can generate aneuploidies and chromosomal instability, which are cellular features associated with cancer initiation and progression. Maintaining centromere integrity is thus essential for genome stability. However, the centromere itself is prone to DNA breaks, likely due to its intrinsically fragile nature. Centromeres are complex genomic loci that are composed of highly repetitive DNA sequences and secondary structures and require the recruitment and homeostasis of a centromere-associated protein network. The molecular mechanisms engaged to preserve centromere inherent structure and respond to centromeric damage are not fully understood and remain a subject of ongoing research. In this article, we provide a review of the currently known factors that contribute to centromeric dysfunction and the molecular mechanisms that mitigate the impact of centromere damage on genome stability. Finally, we discuss the potential therapeutic strategies that could arise from a deeper understanding of the mechanisms preserving centromere integrity. Centromeres are intrinsically fragile due to their repetitive sequence and secondary structures. Increasing evidence point toward the existence of specific mechanisms to prevent centromere-associated genomic instability.