Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224-6825, USA.
Free Radic Biol Med. 2013 Oct;63:115-25. doi: 10.1016/j.freeradbiomed.2013.05.010. Epub 2013 May 14.
Brain tissues from Alzheimer's disease (AD) patients show increased levels of oxidative DNA damage and 7,8-dihydro-8-oxoguanine (8-oxoG) accumulation. In humans, the base excision repair protein 8-oxoguanine-DNA glycosylase (OGG1) is the major enzyme that recognizes and excises the mutagenic DNA base lesion 8-oxoG. Recently, two polymorphisms of OGG1, A53T and A288V, have been identified in brain tissues of AD patients, but little is known about how these polymorphisms may contribute to AD. We characterized the A53T and A288V polymorphic variants and detected a significant reduction in the catalytic activity for both proteins in vitro and in cells. Additionally, the A53T polymorphism has decreased substrate binding, whereas the A288V polymorphism has reduced AP lyase activity. Both variants have decreased binding to known OGG1 binding partners PARP-1 and XRCC1. We found that OGG1(-/-) cells expressing A53T and A288V OGG1 were significantly more sensitive to DNA damage and had significantly decreased survival. Our results provide both biochemical and cellular evidence that A53T and A288V polymorphic proteins have deficiencies in catalytic and protein-binding activities that could be related to the increase in oxidative damage to DNA found in AD brains.
阿尔茨海默病（AD）患者的脑组织显示出氧化 DNA 损伤和 7,8-二氢-8-氧鸟嘌呤（8-oxoG）积累水平升高。在人类中，碱基切除修复蛋白 8-氧鸟嘌呤-DNA 糖基化酶（OGG1）是识别和切除诱变 DNA 碱基损伤 8-oxoG 的主要酶。最近，在 AD 患者的脑组织中发现了 OGG1 的两种多态性，即 A53T 和 A288V，但对于这些多态性如何导致 AD 知之甚少。我们对 A53T 和 A288V 多态性变体进行了表征，并在体外和细胞中检测到这两种蛋白的催化活性显著降低。此外，A53T 多态性降低了底物结合，而 A288V 多态性降低了 AP 裂合酶活性。两种变体与已知的 OGG1 结合伙伴 PARP-1 和 XRCC1 的结合均减少。我们发现，表达 A53T 和 A288V OGG1 的 OGG1(-/-)细胞对 DNA 损伤更敏感，存活能力显著降低。我们的结果提供了生化和细胞证据，表明 A53T 和 A288V 多态蛋白在催化和蛋白结合活性方面存在缺陷，这可能与 AD 大脑中发现的氧化损伤增加有关。
