Complex Roles of NEIL1 and OGG1: Insights Gained from Murine Knockouts and Human Polymorphic Variants
Round 1
Reviewer 1 Report
This article provides an interesting review
This review provides an interesting overview of the phenotypes of OGG1 and NEIL1 knockout mouse models. This section is preceded by insightful sections on the structure and mechanisms of action of these enzymes. The text is well written and easy to read. With a few exceptions listed below, the review is well referenced.
The description of specific base damages should also include a discussion of comparative enzyme activity on single-stranded and double-stranded DNA substrates. In addition, what is lacking is a description of redundancy among DNA glycosylases resulting from their overlapping specificities. This redundancy probably explains some of the phenotypes or lack thereof of some mouse knockout models (Ogg1-/-, Neil-/- and double Neil1-/--NTHL1-/- knockouts).
“Intracellularly, OGG1 may also function as a monofunctional glycosylase based on analyses of data from infection of OGG1-proficient gastric epithelial cells with Helicobacter pylori in which there were increased levels of AP sites, while suppression of OGG1 in the same experimental design resulted in a decreased level of AP sites [66].”
I think this statement should be verified, since the aldehyde reactive probe used to measure the abundance of AP site can also react with 5’ and 3’nicked AP sites (1-3). Further treatment with putrescine or ExoIII can distinguish between 5’ and 3’-nicked AP sites. Therefore, results from the above cited study do not demonstrate that OGG1 is a monofunctional glycosylase.
“Although the ultimate objective of the enzymatic processing of damaged bases through BER is error-free restoration of genomic and mitochondrial DNAs…” does not fit with the second part of the sentence “the individual downstream steps are significantly different for repair initiated by NEIL1 and OGG1”. To solve this problem, the first part of this sentence should be deleted, especially that BER is not error-free, Pol β showing a mutation rate higher than 10-4.
Lines 205-208: in addition to these proteins, CUX1, CUX2 and STAB1 were shown to interact with and stimulate the enzymatic activities of OGG1 through their CUT domains (4-7).
The section on metabolic syndrome presents a very informative and detailed description of phenotypes observed in the Neil1-/- and OGG1-/- mice. However, mechanistically it was not immediately obvious how a deficit in the repair of certain altered base could lead to some of the phenotypes and whether most phenotypes resulted from a disfunction specifically in mitochondrial DNA repair. Perhaps adding a brief summary paragraph at the end of this section would help.
Regarding the OGG1tg mouse model, indeed the observations are fascinating, but it also mean that there is sufficient amount of the downstream BER enzymes to complete DNA repair, otherwise the production of AP sites and single-strand breaks would be deleterious. This is in contrast to the observations from other studies showing that overexpression of NTHL1 or OGG1 was deleterious (although the latter observations were made after ionizing radiation) (8,9). Could the author comment on this issue?
The section on the role of OGG1 in transcription should also include a brief description of the results reported in (10,11).
Typos
Line 99: “(TDG) in repair of active DNA demethylation” replace for “(TDG) in a repair process associated with active DNA demethylation”.
Line 193: verify polymerase ??? polymerase
References
Is it according to journal policy to show only the first author? If it is, it is sad. Readers like to see the name of the last author.
1. Nakamura, J., Walker, V.E., Upton, P.B., Chiang, S.Y., Kow, Y.W. and Swenberg, J.A. (1998) Highly sensitive apurinic/apyrimidinic site assay can detect spontaneous and chemically induced depurination under physiological conditions. Cancer Res, 58, 222-225.
2. Nakamura, J. and Swenberg, J.A. (1999) Endogenous apurinic/apyrimidinic sites in genomic DNA of mammalian tissues. Cancer Res., 59, 2522-2526.
3. Nakamura, J., La, D.K. and Swenberg, J.A. (2000) 5'-nicked apurinic/apyrimidinic sites are resistant to beta-elimination by beta-polymerase and are persistent in human cultured cells after oxidative stress. The Journal of biological chemistry, 275, 5323-5328.
4. Ramdzan, Z.M., Vadnais, C., Pal, R., Vandal, G., Cadieux, C., Leduy, L., Davoudi, S., Hulea, L., Yao, L., Karnezis, A.N., Paquet, M., Dankort, D. and Nepveu, A. (2014) RAS Transformation Requires CUX1-Dependent Repair of Oxidative DNA Damage. PLoS Biol, 12, e1001807.
5. Pal, R., Ramdzan, Z.M., Kaur, S., Duquette, P.M., Marcotte, R., Leduy, L., Davoudi, S., Lamarche-Vane, N., Iulianella, A. and Nepveu, A. (2015) CUX2 Functions As an Accessory Factor in the Repair of Oxidative DNA Damage. J. Biol. Chem., 290, 22520-22531.
6. Ramdzan, Z.M., Pal, R., Kaur, S., Leduy, L., Berube, G., Davoudi, S., Vadnais, C. and Nepveu, A. (2015) The function of CUX1 in oxidative DNA damage repair is needed to prevent premature senescence of mouse embryo fibroblasts. Oncotarget, 6, 3613-3626.
7. Kaur, S., Coulombe, Y., Ramdzan, Z.M., Leduy, L., Masson, J.Y. and Nepveu, A. (2016) Special AT-rich Sequence-binding Protein 1 (SATB1) Functions as an Accessory Factor in Base Excision Repair. J Biol Chem, 291, 22769-22780.
8. Yang, N., Chaudhry, M.A. and Wallace, S.S. (2006) Base excision repair by hNTH1 and hOGG1: a two edged sword in the processing of DNA damage in gamma-irradiated human cells. DNA Repair, 5, 43-51.
9. Yang, N., Galick, H. and Wallace, S.S. (2004) Attempted base excision repair of ionizing radiation damage in human lymphoblastoid cells produces lethal and mutagenic double strand breaks. DNA Repair, 3, 1323-1334.
10. Bangalore, D.M. and Tessmer, I. (2022) Direct hOGG1-Myc interactions inhibit hOGG1 catalytic activity and recruit Myc to its promoters under oxidative stress. Nucleic Acids Res, 50, 10385-10398.
11. Perillo, B., Ombra, M.N., Bertoni, A., Cuozzo, C., Sacchetti, S., Sasso, A., Chiariotti, L., Malorni, A., Abbondanza, C. and Avvedimento, E.V. (2008) DNA oxidation as triggered by H3K9me2 demethylation drives estrogen-induced gene expression. Science, 319, 202-206.
Author Response
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Author Response.docx
Reviewer 2 Report
General comment
Professor Stephen Lloyd offers a nice and well-documented review of the state of knowledge about the role of OGG1 and NEIL1 proteins in maintaining the integrity of genetic information contained in nuclear and mitochondrial DNA. These two DNA glycosylases have long been known to be the enzymes that initiate the repair of oxidized DNA bases in the base excision repair (BER) system. The objective of this review is to try to better clarify the respective roles of OGG1 and NEIL1 by gathering the evidence obtained from various phenotypes of KO and transgenic mice but also from observed predisposition to different diseases associated with polymorphic variants of these proteins.
In spite of the numerous contradictory data found in the abundant literature of these two proteins, the author manages to make an honest and constructive synthesis that will undoubtedly be very useful to the research community working on DNA repair and mutagenesis mechanisms and on human diseases possibly associated with OGG1 and NEIL1 dysfunction/modulation.
A few remarks
1) Even if this review is focussed on the human OGG1 protein (hOGG1), it seems to me that it would be good to recall in the text that the protein was first discovered in the yeast S. cerevisiae (yOGG1) by functional complementation of a deficient Fpg/MutY bacterial strain (Fpg, also called MutM, being the bacterial functional (but not structural) homologue of OGG1) (Auffret van der Kemp et al., PNAS (1996) Vol. 93, pp. 5197-5202). This discovery made it possible to clone the human gene very easily afterwards by inspecting the human genome sequence partly known.
2) In paragraph 5.3 discussing the role of OGG1 as a transcriptional regulator of many pro-inflammatory genes in response to oxidative DNA stress, the interest of targeting OGG1 with inhibitors in certain pathological contexts is mentioned by the author. For completeness and to echo the previous paragraph 5.2 dealing with the effect of OGG1 overexpression in transgenic mice, the author also mentions in paragraph 6.4 the therapeutic potential of OGG1 modulators capable of stimulating the enzyme for applications in neurodegenerative diseases (Alzheimer for ex) but not only. These activators would probably be also very useful in the treatment of metabolic syndromes such as obesity. In this regard, it seems to me that the first paper to identify OGG1 activators was by Morland et al., DNA Repair. Mar2005, Vol. 4 Issue 3, p381-387. 7p. DOI: 10.1016/j.dnarep.2004.11.002. It should perhaps be cited.
3) In paragraph 5.1. regarding the phenotype of OGG1 and NEIL1 KO mice in cancer, the sentences “Germane to Neil1’s role in maintaining genomic stability, expansion of trinucleotide repeats that are associated with the development of Huntington’s disease are significantly reduced in Neil1-/- mice relative to control [99]. Further, this study demonstrated that Neil1 loss reduced germline expansion in males and overall concluded that Neil1 plays a role in germline and Huntington’s disease trinucleotide repeat expansion.” does not seem to be well placed in the text. They could be included in section 5.4 with another title such as "OGG1 and NEIL1 in neurodegenerative diseases" adding that OGG1 is also proposed to be involved in triggering CAG repeat expansion in Huntington's disease as evidenced by these four publications:
- Kovtun, I.V., et al., OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells. Nature, 2007. 447(7143): p. 447-52.
- Goula, A.V., et al., Stoichiometry of base excision repair proteins correlates with increased somatic CAG instability in striatum over cerebellum in Huntington's disease transgenic mice. PLoS Genet, 2009. 5(12): p. e1000749.
- Goula, A.V. and K. Merienne, Abnormal base excision repair at trinucleotide repeats associated with diseases: a tissue-selective mechanism. Genes (Basel), 2013. 4(3): p. 375-87.
- Budworth, H., et al., Suppression of Somatic Expansion Delays the Onset of Pathophysiology in a Mouse Model of Huntington's Disease. PLoS Genet, 2015. 11(8): p. e1005267.
Author Response
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