Duan Shunlei, Han Xuerui, Akbari Mansour, Croteau Deborah L, Rasmussen Lene Juel, Bohr Vilhelm A
Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, DK-2200 Copenhagen, Denmark.
Laboratory of Molecular Gerontology, National Institute on Aging, 251 Bayview Blvd, Baltimore, MD, 21224, USA.
Nucleic Acids Res. 2020 Jul 9;48(12):6530-6546. doi: 10.1093/nar/gkaa392.
OGG1 initiated base excision repair (BER) is the major pathway for repair of oxidative DNA base damage 8-oxoguanine (8-oxoG). Here, we report that RECQL4 DNA helicase, deficient in the cancer-prone and premature aging Rothmund-Thomson syndrome, physically and functionally interacts with OGG1. RECQL4 promotes catalytic activity of OGG1 and RECQL4 deficiency results in defective 8-oxoG repair and increased genomic 8-oxoG. Furthermore, we show that acute oxidative stress leads to increased RECQL4 acetylation and its interaction with OGG1. The NAD+-dependent protein SIRT1 deacetylates RECQL4 in vitro and in cells thereby controlling the interaction between OGG1 and RECQL4 after DNA repair and maintaining RECQL4 in a low acetylated state. Collectively, we find that RECQL4 is involved in 8-oxoG repair through interaction with OGG1, and that SIRT1 indirectly modulates BER of 8-oxoG by controlling RECQL4-OGG1 interaction.
OGG1起始的碱基切除修复（BER）是修复氧化性DNA碱基损伤8-氧代鸟嘌呤（8-oxoG）的主要途径。在此，我们报告，在易患癌症且早衰的罗思蒙德-汤姆森综合征中功能缺陷的RECQL4 DNA解旋酶，在物理和功能上与OGG1相互作用。RECQL4促进OGG1的催化活性，RECQL4缺陷导致8-oxoG修复缺陷和基因组8-oxoG增加。此外，我们表明急性氧化应激导致RECQL4乙酰化增加及其与OGG1的相互作用。NAD+依赖的蛋白SIRT1在体外和细胞中使RECQL4去乙酰化，从而在DNA修复后控制OGG1与RECQL4之间的相互作用，并使RECQL4维持在低乙酰化状态。我们总体发现，RECQL4通过与OGG1相互作用参与8-oxoG修复，并且SIRT1通过控制RECQL4-OGG1相互作用间接调节8-oxoG的碱基切除修复。
