O'Sullivan Roderick J, Greenberg Roger A
Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA
Department of Cancer Biology, Penn Center for Genome Integrity, Basser Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
Cold Spring Harb Perspect Biol. 2025 Jan 7;17(1):a041690. doi: 10.1101/cshperspect.a041690.
In recent years, significant advances have been made in understanding the intricate details of the mechanisms underlying alternative lengthening of telomeres (ALT). Studies of a specialized DNA strand break repair mechanism, known as break-induced replication, and the advent of telomere-specific DNA damaging strategies and proteomic methodologies to profile the ribonucleoprotein composition of telomeres enabled the discovery of networks of proteins that coordinate the stepwise homology-directed DNA repair and DNA synthesis processes of ALT. These networks couple mediators of homologous recombination, DNA template-switching, long-range template-directed DNA synthesis, and DNA strand resolution with SUMO-dependent liquid condensate formation to create discrete nuclear bodies where telomere extension occurs. This review will discuss the recent findings of how these networks may cooperate to mediate telomere extension by the ALT mechanism and their impact on telomere function and integrity in ALT cancer cells.
近年来，在理解端粒替代延长（ALT）潜在机制的复杂细节方面取得了重大进展。对一种称为断裂诱导复制的特殊DNA链断裂修复机制的研究，以及端粒特异性DNA损伤策略和蛋白质组学方法的出现，用于分析端粒的核糖核蛋白组成，使得发现了协调ALT逐步同源性导向DNA修复和DNA合成过程的蛋白质网络。这些网络将同源重组、DNA模板切换、长距离模板导向DNA合成和DNA链解析的介质与SUMO依赖性液体凝聚物形成相结合，以创建发生端粒延长的离散核体。本综述将讨论这些网络如何通过ALT机制协同介导端粒延长的最新发现，以及它们对ALT癌细胞中端粒功能和完整性的影响。
