Telomere Length Regulation Unit, Children's Medical Research Institute, Faculty of Medicine and Health, University of Sydney, Westmead, NSW 2145, Australia.
Open Biol. 2022 Mar;12(3):220011. doi: 10.1098/rsob.220011. Epub 2022 Mar 9.
Telomeres are nucleoprotein structures that cap the ends of linear chromosomes. Telomeric DNA comprises terminal tracts of G-rich tandem repeats, which are inherently difficult for the replication machinery to navigate. Structural aberrations that promote activation of the alternative lengthening of telomeres (ALT) pathway of telomere maintenance exacerbate replication stress at ALT telomeres, driving fork stalling and fork collapse. This form of telomeric DNA damage perpetuates recombination-mediated repair pathways and break-induced telomere synthesis. The relationship between replication stress and DNA repair is tightly coordinated for the purpose of regulating telomere length in ALT cells, but has been shown to be experimentally manipulatable. This raises the intriguing possibility that induction of replication stress can be used as a means to cause toxic levels of DNA damage at ALT telomeres, thereby selectively disrupting the viability of ALT cancers.
端粒是一种核蛋白结构，位于线性染色体的末端。端粒 DNA 由富含 G 的串联重复序列组成，这些序列对于复制机制来说很难进行导航。结构异常会促进端粒维持的替代延长途径（ALT）的激活，加剧 ALT 端粒处的复制压力，导致叉停顿和叉崩溃。这种形式的端粒 DNA 损伤会使重组介导的修复途径和断裂诱导的端粒合成永久化。复制压力和 DNA 修复之间的关系紧密协调，目的是调节 ALT 细胞中的端粒长度，但已被证明在实验上是可操作的。这就提出了一个有趣的可能性，即诱导复制压力可以作为一种手段，在 ALT 端粒处引起毒性水平的 DNA 损伤，从而选择性地破坏 ALT 癌症的活力。
