DNA Base Flipping: A General Mechanism for Writing, Reading, and Erasing DNA Modifications

Hong, Sung Il; Cheng, Xiaodong

doi:10.1007/978-3-319-43624-1_14

Cited by 44 publications

(40 citation statements)

References 117 publications

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“…Although the underlying mechanisms have not been addressed, the same tendencies in base pair preferences have also been observed in other DNA repair enzymes (36,37). Base flipping is a common strategy used for DNA repair or modification enzymes to gain access to the target base (38); however, it is still under debate whether the process of base flipping is catalyzed by enzymes or occurs spontaneously (39). Although it remains unclear whether PfuEndoQ promotes "base breathing" in general (as enzymatic base flipping), it is presumed that spontaneous base flipping is a key for the ) at 60°C for 10 min.…”

Section: Discussionmentioning

confidence: 98%

Molecular Basis of Substrate Recognition of Endonuclease Q from the Euryarchaeon Pyrococcus furiosus

Shiraishi

Iwai

2020

J Bacteriol

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Endonuclease Q (EndoQ), a DNA repair endonuclease, was originally identified in the hyperthermophilic euryarchaeon Pyrococcus furiosus in 2015. EndoQ initiates DNA repair by generating a nick on DNA strands containing deaminated bases and an abasic site. Although EndoQ is thought to be important for maintaining genome integrity in certain bacteria and archaea, the underlying mechanism catalyzed by EndoQ remains unclear. Here, we provide insights into the molecular basis of substrate recognition by EndoQ from P. furiosus (PfuEndoQ) using biochemical approaches. Our results of the substrate specificity range and the kinetic properties of PfuEndoQ demonstrate that PfuEndoQ prefers the imide structure in nucleobases along with the discovery of its cleavage activity toward 5,6-dihydrouracil, 5-hydroxyuracil, 5-hydroxycytosine, and uridine in DNA. The combined results for EndoQ substrate binding and cleavage activity analyses indicated that PfuEndoQ flips the target base from the DNA duplex, and the cleavage activity is highly dependent on spontaneous base flipping of the target base. Furthermore, we find that PfuEndoQ has a relatively relaxed substrate specificity; therefore, the role of EndoQ in restriction modification systems was explored. The activity of the EndoQ homolog from Bacillus subtilis was found not to be inhibited by the uracil glycosylase inhibitor from B. subtilis bacteriophage PBS1, whose genome is completely replaced by uracil instead of thymine. Our findings suggest that EndoQ not only has additional functions in DNA repair but also could act as an antiviral enzyme in organisms with EndoQ. IMPORTANCE Endonuclease Q (EndoQ) is a lesion-specific DNA repair enzyme present in certain bacteria and archaea. To date, it remains unclear how EndoQ recognizes damaged bases. Understanding the mechanism of substrate recognition by EndoQ is important to grasp genome maintenance systems in organisms with EndoQ. Here, we find that EndoQ from the euryarchaeon Pyrococcus furiosus recognizes the imide structure in nucleobases by base flipping, and the cleavage activity is enhanced by the base pair instability of the target base, along with the discovery of its cleavage activity toward 5,6-dihydrouracil, 5-hydroxyuracil, 5-hydroxycytosine, and uridine in DNA. Furthermore, a potential role of EndoQ in Bacillus subtilis as an antiviral enzyme by digesting viral genome is demonstrated.

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Section: Discussionmentioning

confidence: 98%

Molecular Basis of Substrate Recognition of Endonuclease Q from the Euryarchaeon Pyrococcus furiosus

Shiraishi

Iwai

2020

J Bacteriol

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“…All described fluctuations of n max and n min after single 2 H/ 1 H replacement can result in DNA damage due to the slowdown in the rate of bubble forming (especially non-superhelical stress-induced denaturation bubbles having more than 4 base-pairs), including the promoter regions and binding points of specific proteins (e.g., DNA repair enzymes [41,55]), or because of the overwhelming rate of flipping-out DNA nucleobases that can be accompanied by increasing both the speed of modification of their chemical structure and mismatched protein-DNA interaction [56][57][58][59].…”

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confidence: 99%

Inequality in the Frequency of the Open States Occurrence Depends on Single 2H/1H Replacement in DNA

et al. 2020

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In the present study, the effect of 2H/1H isotopic exchange in hydrogen bonds between nitrogenous base pairs on occurrence and open states zones dynamics is investigated. These processes are studied using mathematical modeling, taking into account the number of open states between base pairs. The calculations of the probability of occurrence of open states in different parts of the gene were done depending on the localization of the deuterium atom. The mathematical modeling study demonstrated significant inequality (dependent on single 2H/1H replacement in DNA) among three parts of the gene similar in length of the frequency of occurrence of the open states. In this paper, the new convenient approach of the analysis of the abnormal frequency of open states in different parts of the gene encoding interferon alpha 17 was presented, which took into account both rising and decreasing of them that allowed to make a prediction of the functional instability of the specific DNA regions. One advantage of the new algorithm is diminishing the number of both false positive and false negative results in data filtered by this approach compared to the pure fractile methods, such as deciles or quartiles.

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“…reading, and erasing the modifications (15). The prominent 5mC regulators contain "writers" such as DNA methyltransferase1 (DNMT1), DNMT3A, DNMT3B, "readers" such as methyl-CpG binding domain protein1 (MBD1), MBD2, MBD3, MBD4, methyl-CpG binding protein 2 (MECP2), Nei like DNA glycosylase 1 (NEIL1), Nth like DNA glycosylase 1 (NTHL1), single-strand-selective monofunctional uracil-DNA glycosylase 1 (SMUG1), thymine DNA glycosylase (TDG), ubiquitin-like with PHD and RING finger domains 1 (UHRF1), UHRF2, uracil DNA glycosylase (UNG), zinc finger and BTB domain containing protein 33 (ZBTB33), ZBTB38, ZBTB4 (16) (17) (18).…”

Section: -Methylcytosine (5mc) Is Enzymatically Regulated By Proteinmentioning

confidence: 99%

Molecular and clinical characterization of 5mC regulators in glioma: results of a multicenter study

Zhao

Zhang

Liu

et al. 2020

Preprint

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DNA methylation has been widely reported to associate with the progression of glioma.DNA methylation at the 5 position of cytosine (5-methylcytosine, 5mC), which is regulated by 5mC regulators ("writers", "erasers" and "readers"), is the most critical modification pattern. However, a systematic study on the role of these regulators in glioma is still lacking. In this study, we collected gene expression profiles and corresponding clinical information of gliomas from three independent public datasets.Gene expression of 21 5mC regulators was analyzed and linked to clinicopathological features. A novel molecular classification of glioma was developed using consensus non-negative matrix factorization (CNMF) algorithm, and the tight association with molecular characteristics as well as tumor immune microenvironment was clarified.Sixteen prognostic factors were identified using univariate Cox regression analysis, and a 5mC regulator-based gene signature was further constructed via the least absolute shrinkage and selection operator (LASSO) cox analysis. This risk model was proved as an efficient predictor of overall survival for diffuse glioma, glioblastoma (GBM), and low-grade glioma (LGG) patients in three glioma cohorts. The significant correlation between risk score and intratumoral infiltrated immune cells, as well as immunosuppressive pathways, was found, which explained the difference in clinical outcomes between high and low-risk groups. Finally, a nomogram incorporating the gene signature and other clinicopathological risk factors was established, which might direct clinical decision making. In summary, our work highlights the potential clinical application value of 5mC regulators in prognostic stratification of glioma and their potentialities for developing novel treatment strategies.

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DNA Base Flipping: A General Mechanism for Writing, Reading, and Erasing DNA Modifications

Cited by 44 publications

References 117 publications

Molecular Basis of Substrate Recognition of Endonuclease Q from the Euryarchaeon Pyrococcus furiosus

Molecular Basis of Substrate Recognition of Endonuclease Q from the Euryarchaeon Pyrococcus furiosus

Inequality in the Frequency of the Open States Occurrence Depends on Single 2H/1H Replacement in DNA

Molecular and clinical characterization of 5mC regulators in glioma: results of a multicenter study

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