PRDX1 可抵消由氧化损伤后 DNA 修复活动引发的灾难性端粒断裂事件。

PRDX1 Counteracts Catastrophic Telomeric Cleavage Events That Are Triggered by DNA Repair Activities Post Oxidative Damage.

机构信息

Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.

出版信息

Cell Rep. 2020 Nov 3;33(5):108347. doi: 10.1016/j.celrep.2020.108347.

DOI:10.1016/j.celrep.2020.108347

PMID:33147465

Abstract

Telomeres are prone to damage inflicted by reactive oxygen species (ROS). Oxidized telomeric DNA and nucleotide substrates inhibit telomerase, causing telomere shortening. In addition, ROS can induce telomeric single-strand DNA breaks (SSBs). The peroxiredoxin-PRDX1 is enriched in telomeric chromatin and this counteracts ROS-induced telomere damage. Here, we identify DNA processing after oxidative stress as a main source of telomeric DNA cleavage events in the absence of PRDX1. In PRDX1-depleted cells, poly(ADP-ribose) polymerase (PARP)-dependent telomeric repair is often incomplete, giving persistent SSBs that are converted into telomeric double-strand breaks during replication, leading to rapid telomere shortening. Interestingly, PARP1 inhibition dampens telomere shortening, triggering stabilization of the homologous recombination (HR) factor BRCA1 and RAD51-mediated repair of telomeres. Overall, our results reveal that, in the absence PRDX1, incomplete PARP1-dependent DNA repair and competition between PARP1 and HR cause ROS-induced telomeric catastrophe.

摘要

端粒容易受到活性氧（ROS）造成的损伤。氧化的端粒 DNA 和核苷酸底物会抑制端粒酶，导致端粒缩短。此外，ROS 可以诱导端粒单链 DNA 断裂（SSB）。过氧化物还原酶 PRDX1 在端粒染色质中富集，这可以对抗 ROS 引起的端粒损伤。在这里，我们确定了氧化应激后的 DNA 处理，这是 PRDX1 缺失时端粒 DNA 断裂事件的主要来源。在 PRDX1 耗尽的细胞中，聚（ADP-核糖）聚合酶（PARP）依赖性端粒修复通常是不完全的，导致持续的 SSB，这些 SSB 在复制过程中转化为端粒双链断裂，导致端粒快速缩短。有趣的是，PARP1 抑制剂抑制了端粒缩短，引发了同源重组（HR）因子 BRCA1 的稳定和 RAD51 介导的端粒修复。总的来说，我们的研究结果表明，在缺乏 PRDX1 的情况下，不完全的 PARP1 依赖性 DNA 修复和 PARP1 与 HR 之间的竞争导致了 ROS 诱导的端粒灾难。