Enzymatically inactive OGG1 binds to DNA and steers base excision repair toward gene transcription

Hao, Wenjing; Wang, Jing; Zhang, Yuanhang; Wang, Chenxin; Xia, Lan; Zhang, Wenhe; Zafar, Muhammad Naeem; Kang, Joonsun; Wang, Ruoxi; Bohio, Ameer Ali; Pan, Lang; Zeng, Xianlu; Wei, Min; Boldogh, István; Ba, Xueqing

doi:10.1096/fj.201902243r

Cited by 43 publications

(40 citation statements)

References 70 publications

(265 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent work by Hao et al. ( 48 ) supports the notion that the activity of OGG1 needs to be regulated in order to steer the function of OGG1 toward either DNA repair or gene transcription.…”

Section: Discussionmentioning

confidence: 87%

“…Lastly, our results indicate that positions C146 and C255 are important for the glycosylase activity; thus, a modification at C146 or C255 can activate the pathway in the third scenario, where the nonproductive binding of OGG1 is required for transcription activation ( Figure 7C). Recent work by Hao et al supports the notion that the activity of OGG1 needs to be regulated in order to steer the function of OGG1 towards either DNA repair or gene transcription (48). Cysteine oxidation as a regulation mechanism in DNA repair Previous work has shown that OGG1 is targeted for modification in the presence of cadmium and arsenic, both of which lead to increased levels of ROS and inhibit the activity of OGG1 (31,32).…”

Section: Three Scenarios For Transcriptional Activation Induced By Ogg1mentioning

confidence: 94%

See 1 more Smart Citation

The role of cysteines in the structure and function of OGG1

Wang

Maayah

Sweasy

et al. 2021

Journal of Biological Chemistry

View full text Add to dashboard Cite

8-oxoguanine glycosylase (OGG1) is a base excision repair enzyme responsible for the recognition and removal of 8-oxoguanine, a commonly occurring oxidized DNA modification. OGG1 prevents the accumulation of mutations and regulates the transcription of various oxidative stress-response genes. In addition to targeting DNA, oxidative stress can affect proteins like OGG1 itself, specifically at cysteine residues. Previous work has shown that the function of OGG1 is sensitive to oxidants, with the cysteine residues of OGG1 being the most likely site of oxidation. Due to the integral role of OGG1 in maintaining cellular homeostasis under oxidative stress, it is important to understand the effect of oxidants on OGG1 and the role of cysteines in its structure and function. In this study, we investigate the role of the cysteine residues in the function of OGG1 by mutating and characterizing each cysteine residue. Our results indicate that the cysteines in OGG1 fall into four functional categories: those that are necessary for (1) glycosylase activity (C146 and C255), (2) lyase activity (C140S, C163, C241 and C253), (3) structural stability (C253), and (4) those with no known function (C28 and C75). These results suggest that under conditions of oxidative stress, cysteine can be targeted for modifications, thus altering the response of OGG1 and affecting its downstream cellular functions.

show abstract

“…Recent work by Hao et al. ( 48 ) supports the notion that the activity of OGG1 needs to be regulated in order to steer the function of OGG1 toward either DNA repair or gene transcription.…”

Section: Discussionmentioning

confidence: 87%

Section: Three Scenarios For Transcriptional Activation Induced By Ogg1mentioning

confidence: 94%

The role of cysteines in the structure and function of OGG1

Wang

Maayah

Sweasy

et al. 2021

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Our results showing that a catalytically inactive AAG protein can still induce γH2AX and the DDR suggest that some of the effects of AAG may derive from its ability to recognise damaged bases. Recently, a catalytically inactive mutant of 8-oxoguanine DNA glycosylase (OGG1) was shown to act as a potent regulator of gene expression, and substrate binding was required for OGG1-driven transcriptional activation (53). Similarly, AAG-mediated recognition of alkylated bases could initiate signaling that propagates towards XBP1 splicing.…”

Section: Discussionmentioning

confidence: 99%

A DNA repair-independent role for alkyladenine DNA glycosylase in alkylation-induced unfolded protein response

Milano

Charlier

Andreguetti

et al. 2021

Preprint

View full text Add to dashboard Cite

Alkylating agents damage DNA and proteins and are widely used in cancer chemotherapy. While the cellular responses to alkylation-induced DNA damage have been explored, knowledge of how alkylation damage affects global cellular stress responses is still sparse. Here, we examined the effects of the alkylating agent methylmethane sulfonate (MMS) on gene expression in mouse liver taking advantage of mice deficient in alkyladenine DNA glycosylase (Aag), the enzyme that initiates the repair of alkylated DNA bases. MMS induced a robust transcriptional response in wild-type liver that included markers of the endoplasmic reticulum (ER) stress/unfolded protein response (UPR) known to be controlled by the transcription factor XBP1, a key UPR effector. Importantly, this response is significantly reduced in the Aag knockout. To investigate a potential role for AAG in alkylation-induced UPR, the expression of UPR markers after MMS treatment was interrogated in human glioblastoma cell lines expressing different AAG levels. Alkylation induced the UPR in cells expressing AAG; conversely, AAG knock-down compromised UPR induction and led to a defect in XBP1 activation plus a decrease in the expression of the ER chaperone BiP. To verify that the DNA repair activity of AAG is required for this response, AAG knockdown cells were complemented with wild-type Aag or with a mutant version of the Aag gene producing a glycosylase-deficient AAG protein. As expected, the glycosylase-defective mutant Aag does not fully protect AAG knockdown cells against MMS-induced cytotoxicity. Remarkably, however, alkylation-induced XBP1 activation is fully complemented by the catalytically inactive AAG enzyme. This work establishes that, in addition to its enzymatic activity, AAG has non-canonical functions in alkylation-induced UPR that contribute to the overall cellular response to alkylation.

show abstract

“…The maintenance of 8-oxodG at specific loci, together with accumulating evidence of its dynamics in response to stimuli, strongly suggest a putative regulatory role of 8-oxodG in the genome function [ [17] , [18] , [19] , [20] ]. In particular, activation of the gene transcription by a number of transcription factors has been associated with both localised oxidative damage to DNA [ [21] , [22] , [23] , [24] ] and specific OGG1 recruitment to the target sites in gene promoters [ [25] , [26] , [27] , [28] , [29] , [30] ].…”

Section: Introductionmentioning

confidence: 99%

Regulation of GC box activity by 8-oxoguanine

Müller

Khobta

2021

Redox Biology

View full text Add to dashboard Cite

The oxidation-induced DNA modification 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) was recently implicated in the activation and repression of gene transcription. We aimed at a systematic characterisation of the impacts of 8-oxodG on the activity of a GC box placed upstream from the RNA polymerase II core promoter. With the help of reporters carrying single synthetic 8-oxodG residues at four conserved G:C base pairs (underlined) within the 5′-TG GGCG GAGC-3′ GC box sequence, we identified two modes of interference of 8-oxodG with the promoter activity. Firstly, 8-oxodG in the purine-rich (but not in the pyrimidine-rich) strand caused direct impairment of transcriptional activation. In addition, and independently of the first mechanism, 8-oxodG initiated a decline of the gene expression, which was mediated by the specific DNA glycosylase OGG1. For the different 8-oxodG positions, the magnitude of this effect reflected the excision preferences of OGG1. Thus, 8-oxodG seeded in the pyrimidine-rich strand was excised with the highest efficiency and caused the most pronounced decrease of the promoter activity. Conversely, 8-oxodG in the symmetric position within the same CpG dinucleotide, was poorly excised and induced no decline of the gene expression. Of note, abasic lesions caused gene silencing in both positions. By contrast, an uncleavable apurinic lesion in the pyrimidine-rich strand enhanced the GC box activity, suggesting that the AP endonuclease step provides a switch between the active versus repressed promoter states during base excision repair.

show abstract

Enzymatically inactive OGG1 binds to DNA and steers base excision repair toward gene transcription

Cited by 43 publications

References 70 publications

The role of cysteines in the structure and function of OGG1

The role of cysteines in the structure and function of OGG1

A DNA repair-independent role for alkyladenine DNA glycosylase in alkylation-induced unfolded protein response

Regulation of GC box activity by 8-oxoguanine

Contact Info

Product

Resources

About