De Rosa Mariarosaria, Barnes Ryan P, Nyalapatla Prasanth R, Wipf Peter, Opresko Patricia L
Department of Environmental and Occupational Health, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA.
UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
bioRxiv. 2023 Apr 11:2023.04.10.536247. doi: 10.1101/2023.04.10.536247.
Telomeres are prone to formation of the common oxidative lesion 8-oxoguanine (8oxoG), and the acute production of 8oxoG damage at telomeres is sufficient to drive rapid cellular senescence. OGG1 and MUTYH glycosylases initiate base excision repair (BER) at 8oxoG sites to remove the lesion or prevent mutation. Here, we show OGG1 loss or inhibition, or MUTYH loss, partially rescues telomeric 8oxoG-induced senescence, and loss of both glycosylases results in a near complete rescue. Loss of these glycosylases also suppresses 8oxoG-induced telomere fragility and dysfunction, indicating that single-stranded break (SSB) intermediates arising downstream of glycosylase activity impair telomere replication. The failure to initiate BER in glycosylase-deficient cells suppresses PARylation at SSB intermediates and confers resistance to the synergistic effects of PARP inhibitors on damage-induced senescence. Our studies reveal that inefficient completion of 8oxoG BER at telomeres triggers cellular senescence via SSB intermediates which impair telomere replication and stability.
端粒易于形成常见的氧化损伤产物8-氧代鸟嘌呤（8oxoG），并且端粒处8oxoG损伤的急性产生足以驱动细胞快速衰老。OGG1和MUTYH糖基化酶在8oxoG位点启动碱基切除修复（BER），以去除损伤或防止突变。在此，我们表明OGG1的缺失或抑制，或MUTYH的缺失，可部分挽救端粒8oxoG诱导的衰老，而两种糖基化酶的缺失则导致几乎完全挽救。这些糖基化酶的缺失还抑制了8oxoG诱导的端粒脆性和功能障碍，表明糖基化酶活性下游产生的单链断裂（SSB）中间体损害了端粒复制。糖基化酶缺陷细胞中BER起始的失败抑制了SSB中间体处的聚（ADP-核糖）化，并赋予了对PARP抑制剂对损伤诱导衰老的协同作用的抗性。我们的研究表明，端粒处8oxoG BER的低效完成通过损害端粒复制和稳定性的SSB中间体触发细胞衰老。
