Computational investigations on target-site searching and recognition mechanisms by thymine DNA glycosylase during DNA repair process

Abstract

DNA glycosylase, as one member of DNA repair machineries, plays an essential role in correcting mismatched/ damaged DNA nucleotides by cleaving the N-glycosidic bond between the sugar and target nucleobase through the base excision repair (BER) pathways. Efficient corrections of these DNA lesions are critical for maintaining genome integrity and preventing premature aging and cancers. The target-site searching/recognition mechanisms and the subsequent conformational dynamics of DNA glycosylase, however, remain challenging to be characterized using experimental techniques. In this review, we summarize our recent studies of sequential structural changes of thymine DNA glycosylase (TDG) during the DNA repair process, achieved mostly by molecular dynamics (MD) simulations. Computational simulations allow us to reveal atomic-level structural dynamics of TDG as it approaches the target-site, and pinpoint the key structural elements responsible for regulating the translocation of TDG along DNA. Subsequently, upon locating the lesions, TDG adopts a base-flipping mechanism to extrude the mispaired nucleobase into the enzyme active-site. The constructed kinetic network model elucidates six metastable states during the base-extrusion process and suggests an active role of TDG in flipping the intrahelical nucleobase. Finally, the molecular mechanism of product release dynamics after catalysis is also summarized. Taken together, we highlight to what extent the computational simulations advance our knowledge and understanding of the molecular mechanism underlying the conformational dynamics of TDG, as well as the limitations of current theoretical work.

8-Oxoguanine DNA glycosylase protects cells from senescence via the p53-p21 pathway

“…OGG1 deficiency leads to a reduction in pulmonary fibrosis development, and the mechanism is partly based on the promotion of the TGF/Smad signaling pathway by OGG1, which aggravates the development of pulmonary fibrosis [15] . Aging can lead to a reduction in lung stem cells, mitochondrial dysfunction, oxidative stress damage and telomerase shortening, and ultimately leads to the inability of lung cells to maintain homeostasis, which plays important roles in the occurrence and development of IPF, chronic obstructive pulmonary disease and other pulmonary diseases [16] . However, it is worth noting that cellular senescence may exert a positive and negative regulatory role in organ fibrosis.…”

“…8-Oxo-7,8-dihydroguanine (8-oxo-G) is the main product of oxidative DNA damage in cells and one of the most common types of endogenously generated mutagenic base damage [ 11 , 12 ]. The corresponding DNA repair enzyme is 8-oxoguanine DNA glycosylase (OGG1), a DNA repair glycosylase that localizes to both the nucleus and mitochondria [ 13 – 16 ], and it has been shown to activate α-SMA polymerization and to increase the levels of α-SMA exposure to stress fibres [17] . OGG1 inhibition mediated by EGFR is involved in the cell transformation induced by wood dust exposure [18] .…”