Microhomology-Mediated End-Joining Chronicles: Tracing the Evolutionary Footprints of Genome Protection.

IF 11.4 1区 生物学 Q1 CELL BIOLOGY
Agnel Sfeir, Marcel Tijsterman, Mitch McVey
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引用次数: 0

Abstract

The fidelity of genetic information is essential for cellular function and viability. DNA double-strand breaks (DSBs) pose a significant threat to genome integrity, necessitating efficient repair mechanisms. While the predominant repair strategies are usually accurate, paradoxically, error-prone pathways also exist. This review explores recent advances and our understanding of microhomology-mediated end joining (MMEJ), an intrinsically mutagenic DSB repair pathway conserved across organisms. Central to MMEJ is the activity of DNA polymerase theta (Polθ), a specialized polymerase that fuels MMEJ mutagenicity. We examine the molecular intricacies underlying MMEJ activity and discuss its function during mitosis, where the activity of Polθ emerges as a last-ditch effort to resolve persistent DSBs, especially when homologous recombination is compromised. We explore the promising therapeutic applications of targeting Polθ in cancer treatment and genome editing. Lastly, we discuss the evolutionary consequences of MMEJ, highlighting its delicate balance between protecting genome integrity and driving genomic diversity.

微观同源性介导的末端连接编年史:追踪基因组保护的进化足迹。
遗传信息的保真度对细胞的功能和活力至关重要。DNA 双链断裂(DSB)对基因组的完整性构成重大威胁,因此需要高效的修复机制。虽然主要的修复策略通常是准确的,但矛盾的是,也存在容易出错的途径。这篇综述探讨了微同源物介导的末端连接(MMEJ)的最新进展和我们对它的理解,MMEJ 是一种内在突变的 DSB 修复途径,在各种生物中都是一致的。MMEJ的核心是DNA聚合酶θ(Polθ)的活性,它是一种特殊的聚合酶,能激发MMEJ的致突变性。我们研究了 MMEJ 活性背后错综复杂的分子机制,并讨论了它在有丝分裂过程中的功能,在有丝分裂过程中,Polθ 的活性是解决持续性 DSB 的最后努力,尤其是在同源重组受到损害时。我们探讨了以 Polθ 为靶点在癌症治疗和基因组编辑中的应用前景。最后,我们讨论了 MMEJ 的进化后果,强调了它在保护基因组完整性和推动基因组多样性之间的微妙平衡。
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来源期刊
CiteScore
19.50
自引率
0.00%
发文量
21
期刊介绍: The Annual Review of Cell and Developmental Biology, established in 1985, comprehensively addresses major advancements in cell and developmental biology. Encompassing the structure, function, and organization of cells, as well as the development and evolution of cells in relation to both single and multicellular organisms, the journal explores models and tools of molecular biology. As of the current volume, the journal has transitioned from gated to open access through Annual Reviews' Subscribe to Open program, making all articles published under a CC BY license.
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