Abstract:
Cancer cells maintain telomeres by upregulating telomerase or alternative lengthening of telomeres (ALT) via homology-directed repair at telomeric DNA breaks. 8-Oxoguanine (8oxoG) is a highly prevalent endogenous DNA lesion in telomeric sequences, altering telomere structure and telomerase activity, but its impact on ALT is unclear. Here, we demonstrate that targeted 8oxoG formation at telomeres stimulates ALT activity and homologous recombination specifically in ALT cancer cells. Mechanistically, an acute 8oxoG induction increases replication stress, as evidenced by increased telomere fragility and ATR kinase activation at ALT telomeres. Furthermore, ALT cells are more sensitive to chronic telomeric 8oxoG damage than telomerase-positive cancer cells, consistent with increased 8oxoG-induced replication stress. However, telomeric 8oxoG production in G2 phase, when ALT telomere elongation occurs, impairs telomeric DNA synthesis. Our study demonstrates that a common oxidative base lesion has a dual role in regulating ALT depending on when the damage arises in the cell cycle.
摘要:
癌细胞通过上调端粒酶或通过同源定向修复端粒DNA断裂来延长端粒(ALT)来维持端粒。8-Oxoguanine(8oxoG)是端粒序列中高度普遍的内源性DNA损伤,改变端粒结构和端粒酶活性,但其对ALT的影响尚不清楚。这里,我们证明在端粒的靶向8oxoG形成刺激ALT活性和特异性ALT癌细胞的同源重组。机械上,急性8oxoG诱导增加复制应激,正如ALT端粒的端粒脆性和ATR激酶激活增加所证明的那样。此外,ALT细胞对慢性端粒8oxoG损伤比端粒酶阳性癌细胞更敏感,与8oxoG诱导的复制应激增加一致。然而,G2期端粒8oxoG的产生,当ALT端粒伸长发生时,损害端粒DNA合成。我们的研究表明,常见的氧化碱基损伤在调节ALT方面具有双重作用,具体取决于何时在细胞周期中出现损伤。