Position-Dependent Effect of Guanine Base Damage and Mutations on Telomeric G-Quadruplex and Telomerase Extension.
Position-Dependent Effect of Guanine Base Damage and Mutations on Telomeric G-Quadruplex and Telomerase Extension.
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DOI：
10.1021/acs.biochem.0c00434
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发表时间：
2020-07-21
期刊：
影响因子：
2.9
通讯作者：
Myong S
中科院分区：
文献类型：
--
作者：
Lee HT;Sanford S;Paul T;Choe J;Bose A;Opresko PL;Myong S
端粒由于其高鸟嘌呤含量，是诱变、氧化和甲基化碱基损伤的热点。我们使用单分子荧光共振能量转移检测和生化测定来确定不同位置和类型的鸟嘌呤损伤和突变如何改变端粒G-四链体结构和端粒酶活性。我们比较了15种修饰，包括8-氧代鸟嘌呤（8 oxoG），O-6-甲基鸟嘌呤（O 6 mG），以及端粒G-四链体3′端鸟嘌呤位置的所有三种可能的点突变（G到A，T和C），这是端粒酶的关键接入点。我们发现G-四链体结构不稳定性的诱导顺序为C < T < A ≤ 8 oxoG <O 6 mG，其中O 6 mG引起的扰动远远超过其他碱基改变引起的扰动。对于所有的碱基修饰，中央G位置是最不稳定的三个终端鸟嘌呤。虽然8 oxoG和O 6 mG的结构破坏导致端粒酶结合和延伸活性的伴随增加，但由于端粒突出端和端粒酶RNA模板之间的退火被破坏，点突变（A、T和C）的结构扰动没有。重新定位相同的突变远离末端鸟嘌呤引起G-四链体结构不稳定和端粒酶活性升高。我们的研究结果表明，单碱基修饰如何以位置依赖的方式驱动结构改变和端粒延长。此外，我们的研究结果表明，端粒DNA损伤的长期和遗传效应，可导致端粒延长，这可能有助于肿瘤的发生。
Telomeres are hot spots for mutagenic oxidative and methylation base damage due to their high guanine content. We used single-molecule fluorescence resonance energy transfer detection and biochemical assays to determine how different positions and types of guanine damage and mutations alter telomeric G-quadruplex structure and telomerase activity. We compared 15 modifications, including 8-oxoguanine (8oxoG), O-6-methylguanine (O6mG), and all three possible point mutations (G to A, T, and C) at the 3′ three terminal guanine positions of a telomeric G-quadruplex, which is the critical access point for telomerase. We found that G-quadruplex structural instability was induced in the order C < T < A ≤ 8oxoG < O6mG, with the perturbation caused by O6mG far exceeding the perturbation caused by other base alterations. For all base modifications, the central G position was the most destabilizing among the three terminal guanines. While the structural disruption by 8oxoG and O6mG led to concomitant increases in telomerase binding and extension activity, the structural perturbation by point mutations (A, T, and C) did not, due to disrupted annealing between the telomeric overhang and the telomerase RNA template. Repositioning the same mutations away from the terminal guanines caused both G-quadruplex structural instability and elevated telomerase activity. Our findings demonstrate how a single-base modification drives structural alterations and telomere lengthening in a position-dependent manner. Furthermore, our results suggest a long-term and inheritable effect of telomeric DNA damage that can lead to telomere lengthening, which potentially contributes to oncogenesis.
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DOI：
10.1196/annals.1297.047
发表时间：
2004-01-01
期刊：
STRATEGIES FOR ENGINEERED NEGLIGIBLE SENESCENCE: WHY GENUINE CONTROL OF AGING MAY BE FORESEEABLE
影响因子：
--
作者：
Kawanishi, S;Oikawa, S
通讯作者：
Oikawa, S
影响因子：
14.9
作者：
Ambrus A;Chen D;Dai J;Bialis T;Jones RA;Yang D
通讯作者：
Yang D
影响因子：
16.8
作者：
Fouquerel, Elise;Lormand, Justin;Bose, Arindam;Lee, Hui-Ting;Kim, Grace S.;Li, Jianfeng;Sobol, Robert W.;Freudenthal, Bret D.;Myong, Sua;Opresko, Patricia L.
通讯作者：
Opresko, Patricia L.
影响因子：
14.9
作者：
Bauer NC;Corbett AH;Doetsch PW
通讯作者：
Doetsch PW
影响因子：
14.9
作者：
Dai J;Punchihewa C;Ambrus A;Chen D;Jones RA;Yang D
通讯作者：
Yang D