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8-氧代鸟嘌呤破坏G-四链体DNA稳定性并调节FANCJ AKKQ肽结合。

8-Oxoguanine Disrupts G-Quadruplex DNA Stability and Modulates FANCJ AKKQ Peptide Binding.

作者信息

Campbell Laura, Lowran Kaitlin, Cismas Emma, Wu Colin G

机构信息

Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.

Department of Chemistry, Oakland University, Rochester, MI 48309, USA.

出版信息

Molecules. 2025 Aug 20;30(16):3424. doi: 10.3390/molecules30163424.

DOI:10.3390/molecules30163424
PMID:40871576
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12388576/
Abstract

Guanine-rich nucleic acid sequences can adopt G-quadruplex (G4) structures, which pose barriers to DNA replication and repair. The FANCJ helicase contributes to genome stability by resolving these structures, a function linked to its G4-binding site that features an AKKQ amino acid motif. This site is thought to recognize oxidatively damaged G4, specifically those containing 8-oxoguanine (8oxoG) modifications. We hypothesize that FANCJ AKKQ recognition of 8oxoG-modified G4s (8oxoG4s) depends on the sequence context, the position of the lesion within the G4, and overall structural stability. Using fluorescence spectroscopy, we measured the binding affinities of a FANCJ AKKQ peptide for G4s formed by (GGGT), (GGGTT), and (TTAGGG) sequences. G4 conformation and thermal stability were assessed by circular dichroism spectroscopy. Each sequence was modified to include a single 8oxoG at the first (8oxo1), third (8oxo3), or fifth (8oxo5) guanine position. In potassium chloride (KCl), the most destabilized structures were (GGGT) 8oxo1, (GGGTT) 8oxo1, and (TTAGGG) 8oxo5. In sodium chloride (NaCl), the most destabilized were (GGGT) 8oxo1, (GGGTT) 8oxo5, and (TTAGGG) 8oxo5. FANCJ AKKQ binding affinities varied according to damage position and sequence context, with notable differences for (GGGT) in KCl and (TTAGGG) in NaCl. These findings support a model in which FANCJ binding to G4 and 8oxoG4 structures is modulated by both the oxidative damage position and the G4 local sequence environment.

摘要

富含鸟嘌呤的核酸序列可形成G-四链体（G4）结构，这些结构对DNA复制和修复构成障碍。FANCJ解旋酶通过解开这些结构来促进基因组稳定性，该功能与其具有AKKQ氨基酸基序的G4结合位点相关。该位点被认为可识别氧化损伤的G4，特别是那些含有8-氧代鸟嘌呤（8oxoG）修饰的G4。我们假设FANCJ的AKKQ对8oxoG修饰的G4（8oxoG4s）的识别取决于序列背景、G4内损伤的位置以及整体结构稳定性。利用荧光光谱法，我们测量了FANCJ的AKKQ肽对由（GGGT）、（GGGTT）和（TTAGGG）序列形成的G4的结合亲和力。通过圆二色光谱法评估G4构象和热稳定性。每个序列都被修饰为在第一个（8oxo1）、第三个（8oxo3）或第五个（8oxo5）鸟嘌呤位置包含一个单一的8oxoG。在氯化钾（KCl）中，最不稳定的结构是（GGGT）8oxo1、（GGGTT）8oxo1和（TTAGGG）8oxo5。在氯化钠（NaCl）中，最不稳定的是（GGGT）8oxo1、（GGGTT）8oxo5和（TTAGGG）8oxo5。FANCJ的AKKQ结合亲和力因损伤位置和序列背景而异，在KCl中的（GGGT）和NaCl中的（TTAGGG）有显著差异。这些发现支持了一个模型，即FANCJ与G4和8oxoG4结构的结合受到氧化损伤位置和G4局部序列环境的调节。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d1df/12388576/6bfc00b6cfe9/molecules-30-03424-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d1df/12388576/80f1b8a2cc6b/molecules-30-03424-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d1df/12388576/7b3eade30ffa/molecules-30-03424-g003.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d1df/12388576/58a6a5efd385/molecules-30-03424-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d1df/12388576/f250e9fcf026/molecules-30-03424-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d1df/12388576/1410fd637349/molecules-30-03424-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d1df/12388576/1d5cb4d27874/molecules-30-03424-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d1df/12388576/11950a60c118/molecules-30-03424-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d1df/12388576/6bfc00b6cfe9/molecules-30-03424-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d1df/12388576/80f1b8a2cc6b/molecules-30-03424-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d1df/12388576/295247736fe9/molecules-30-03424-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d1df/12388576/7b3eade30ffa/molecules-30-03424-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d1df/12388576/3a21ee2954a7/molecules-30-03424-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d1df/12388576/58a6a5efd385/molecules-30-03424-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d1df/12388576/f250e9fcf026/molecules-30-03424-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d1df/12388576/1410fd637349/molecules-30-03424-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d1df/12388576/1d5cb4d27874/molecules-30-03424-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d1df/12388576/11950a60c118/molecules-30-03424-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d1df/12388576/6bfc00b6cfe9/molecules-30-03424-g010.jpg

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