Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This review manuscript focuses on the structure, PTM and protein-protein interactions of OGG1 and MUTYH and its potential new roles. It helps readers to know the progress of these molecules. This manuscript is well organized. The topic is important to the field. It does not address the specific gap in the field, for this manuscript reviews the current research development. The conclusion consistent with the evidence presented and provide a comprehensive review for the current field. Most of the references are appropriate.

 

Major Concerns: The context of the manuscript is large, and it is difficult to catch the whole context. It can be used to publish 2 reviews. The authors need to trim manuscript to make it short and concise. The basic mechanisms and functions of different PTMs is well known, the authors may delete these introductions.

Minor concerns: 1, reference 128, it is a misleading citation. The authors claim that CHIP ubiquitinates Polß in reference 128. This finding can’t be confirmed in paper (2014 Nat Commu; 5:5513) that suggested that CHIP may ubiquitinate XRCC1 but not Polß. Please correct it.

2, Line 572-573: The authors cite the references to claim that these proteins can be PARylated. In fact, Polß has never been confirmed that it can be parylated. Some of other proteins may not also be parylated. The authors need to confirm it.

3, In the concluding remarks part, the authors need to present the unresolved issues faced in the field.

Author Response

Reviewer 1 Comments and Suggestions are shown in black letters, and the corresponding responses in blue. 

This review manuscript focuses on the structure, PTM and protein-protein interactions of OGG1 and MUTYH and its potential new roles. It helps readers to know the progress of these molecules. This manuscript is well organized. The topic is important to the field. It does not address the specific gap in the field, for this manuscript reviews the current research development. The conclusion consistent with the evidence presented and provide a comprehensive review for the current field. Most of the references are appropriate.

Major Concerns: The context of the manuscript is large, and it is difficult to catch the whole context. It can be used to publish 2 reviews. The authors need to trim manuscript to make it short and concise. The basic mechanisms and functions of different PTMs is well known; the authors may delete these introductions.

Response: We thank this comment and totally understand that the length of the original manuscript might represent an issue, mainly due to redundancy in the text. Based on this comment, we reduced the redundancy and summarized some sections in a concise manner, resulting in a significant reduction of the length of the revised version of the manuscript. The original document had 1224 lines (33 pages without references), and the revised version has 857 lines (24 pages). We appreciate the encouragement to trim the manuscript, and now we think that the fluency is considerably better.

Minor concerns: 1, reference 128, it is a misleading citation. The authors claim that CHIP ubiquitinates Polß in reference 128. This finding can’t be confirmed in paper (2014 Nat Commu; 5:5513) that suggested that CHIP may ubiquitinate XRCC1 but not Polß. Please correct it.

Response: We appreciate this observation. As a result of the manuscript trimming, the referred section was deleted.

2, Line 572-573: The authors cite the references to claim that these proteins can be PARylated. In fact, Polß has never been confirmed that it can be parylated. Some of other proteins may not also be parylated. The authors need to confirm it.

Response: We appreciate this observation. As a result of the manuscript trimming, the referred section was deleted.

3, In the concluding remarks part, the authors need to present the unresolved issues faced in the field.

Response: We agree and included the following section at the end of the Concluding remarks: “Finally, there are still questions regarding the mechanisms these enzymes utilize. For example, understanding a general mechanism of product turnover may shed light on the implication of OG repair in telomeric instability and apoptosis. Additionally, understanding BERosome formation could present novel opportunities for therapeutic intervention.”

Reviewer 2 Report

Comments and Suggestions for Authors

Comments to authors:

The manuscript of a review article, which was written by Dr. Ana P. Gómez-Ramírez et al, is interesting, describing the biological significances of the base excision repair factors, OGG1 and MUTYH, discussing their biological functions, structures and expression controlling mechanisms. I think it would be worth publishing. However, authors should make best effort to shorten the manuscript as possible to avoid redundant expressions. Moreover, Figures and Tables, which do not seem to be shown with enough explanations, are not easy to understand. Therefore, I suggest authors edit text and Figures with appropriate explanations before publication.

 

Recommendation: Major revision

 

General comments

In general, this manuscript is well written with many references that showed biological significance of the OGG1 and the MUTYH. Authors draw Figures that include both OGG1 and MUTYH within. However, descriptions for MUTYH is considerably apart from the Figures. I recommend authors separate pictures of the OGG1 and the MUTYH to redraw two Figures to place them on the right places.

Honestly, after reading the whole text, I felt if this review article could be better edited as two different papers, one for the OGG1 and the other for the MUTYH. Following are the comments only for the OGG1 (from p1 to p19).

 

Specific comments

1. Introduction (p1-3)

Figure 1: In A), ROS and Replication is typed in black. Therefore, they should be the same in B). Additionally, on the legend, proteins, including FEN1, pol lambda, APE1, DNA lig III, pol beta, are not explained at all. They seem to be explained in detail on the text, though. However, in general review articles, Figures are to be completed with minimum information with appropriate references. That will greatly reduce the explanations in the text. Authors had better make best effort to reduce the description in Introduction.

 

2. OGG1 and Mutyh as Part of the Human Go Repair Sys-Tem (p3 and 4)

This section could be included in the Introduction section.

 

3. OGG1 (p4-19)

Figure 2A: Readers cannot understand each DNA-binding proteins which are indicated by different colors. At least, their names with minimum explanations should be indicated in A) or noted on the legend.

In this review, authors featured the transcription regulatory functions of the OGG1 especially on the immunological responses. Although authors described the relationships between OGG1 and NF-kappaB, dysregulation of BER could simultaneously affect immune responses as well. If the main function of the OGG1 is upon the BER system, authors had better reconsider the biological consequences that come directly from DNA damage that are not mediated by OGG1.

Moreover, regarding the recognition of the G-quartet structures, which are known to be formed on the specific regions of chromosomes, including telomeres, authors might better note some experimentally shown evidence to conclude that OGG1 recognizes to bind to. Of course, how that was shown should be explained in detail.

Figure 3: Number of human chromosomes should be indicated for each gene. Authors should add explanations for better understanding of the Figure. For example, what is the TF network? In the present form, I think readers cannot understand at all. As I wrote above, Figures but with minimum legend to be understood by themselves should be made, without a need to read the text. That will surely shorten the text. Moreover, in Figure 3, the direction of the MUTYH gene from 5’- to 3’ is reversed compared to OGG1. Anyway, 5’-UTR/3’-UTR should be indicated for the MUTYH gene.

P9 – p11 (L239-340): Authors reviewed the OGG1 promoter and the epigenetic regulations. The sections 3.2.1 and 3.2.2 would better be just included in 3.2 as “OGG1 gene structure and regulation”.

Figure 5: In the legend, explanations for better understanding this Figure are required. For example, how was the ribbon model drawn? How was the OGG1 network obtained? The information should be given in the legend.

Table 1: The title of the Table should be placed on the Top. Title should not be included in the Table itself. In short, the most upper line should be eliminated. Additionally, this Table needs to be separated into two, to make Table 1 and 2, for OGG1 and MUTYH, respectively. The newly made Tables need legends, and the text could be greatly reduced.

 

4. MUTYH (p19-29)

I advise authors themselves confirm Figures for MUTYH, which were separated from Figures 1 to 5, to be appropriately edited and placed in the appropriate places in this section.

Figure 6: This Figure and the related descriptions seem to be better moved to the Introduction section because it illustrates one of the biological functions that OGG1 and MUTYH are involved in.

I felt that the description is heavily redundant to understand essential things. I strongly encourage authors to avoid redundant expressions but remain essential descriptions and that will improve this manuscript.

 

5. Concluding Remarks (p29)

As mentioned above, this section also needs to be shortened while remaining essential information. I advise authors to make the conclusion as an illustration or a cartoon with minimum sentences.

 

Minor comments

Generally, gene names should be typed in italic to avoid misunderstandings with protein names. I recommend authors confirm all gene names and Gene IDs at the NIH Gene (https:// www.ncbi.nlm.nih.gov/gene/). Authors might better recheck all through the text.

Page 3, L88: OGG1 and Mutyh as Part of the Human Go Repair Sys-Tem; OGG1 and MUTYH as Part of the Human GO Repair System

Page 29-41: I think References are not formatted as MDPI journal form. Authors had better format themselves. While doing so, corrections could be made as well.

Author Response

Reviewer's comments and suggestions are shown in black letters and Authors's responses in blue. 

Comments to authors:

The manuscript of a review article, which was written by Dr. Ana P. Gómez-Ramírez et al, is interesting, describing the biological significances of the base excision repair factors, OGG1 and MUTYH, discussing their biological functions, structures and expression controlling mechanisms. I think it would be worth publishing. However, authors should make best effort to shorten the manuscript as possible to avoid redundant expressions. Moreover, Figures and Tables, which do not seem to be shown with enough explanations, are not easy to understand. Therefore, I suggest authors edit text and Figures with appropriate explanations before publication.

Recommendation: Major revision

General comments

In general, this manuscript is well written with many references that showed biological significance of the OGG1 and the MUTYH. Authors draw Figures that include both OGG1 and MUTYH within. However, descriptions for MUTYH is considerably apart from the Figures. I recommend authors separate pictures of the OGG1 and the MUTYH to redraw two Figures to place them on the right places.

Response: We appreciate this comment. However, given that both OGG1 and MUTYH have complementary repair activities correcting OG:C and OG:A DNA lesions, we think that showing a scheme with both OGG1- and MUTYH-mediated BER is appropriate, allowing to portray a full picture of the repair pathway. Therefore, we suggest leaving it as it is.

Honestly, after reading the whole text, I felt if this review article could be better edited as two different papers, one for the OGG1 and the other for the MUTYH.

Response: We thank this comment and totally understand that the length of the original manuscript might represent an issue, mainly due to redundancy in the text. Based on this comment, we reduced the redundancy and summarized some sections in a concise manner, resulting in a significant reduction of the length of the revised version of the manuscript. The original document had 1224 lines (33 pages without references), and the revised version has 857 lines (24 pages). We appreciate the encouragement to trim the manuscript, and now we think that the fluency is considerably better.

Following are the comments only for the OGG1 (from p1 to p19). 

Specific comments

1. Introduction (p1-3)

Figure 1: In A), ROS and Replication is typed in black. Therefore, they should be the same in B).

Response: Corrected as suggested.

Additionally, on the legend, proteins, including FEN1, pol lambda, APE1, DNA lig III, pol beta, are not explained at all. They seem to be explained in detail on the text, though. However, in general review articles, Figures are to be completed with minimum information with appropriate references. That will greatly reduce the explanations in the text. Authors had better make best effort to reduce the description in Introduction.

Response: We appreciate the suggestion. Considering this comment and the following one, we decided to combine the previous section 2 (OGG1 and Mutyh as Part of the Human Go Repair System) and the introduction. Moreover, we take advantage of the figure capture of Figure 1 to describe in more detail the MUTYH- and OGG1-mediated BER. 

1. OGG1 and Mutyh as Part of the Human Go Repair Sys-Tem (p3 and 4)

This section could be included in the Introduction section.

Response: Corrected as suggested.

1. OGG1 (p4-19)

Figure 2A: Readers cannot understand each DNA-binding proteins which are indicated by different colors. At least, their names with minimum explanations should be indicated in A) or noted on the legend.

Response: Thanks for the comment. We modified the figure, just showing OGG1 in blue, NF-kB in green, and the whole transcriptional machinery in pink, to avoid confusion.

In this review, authors featured the transcription regulatory functions of the OGG1 especially on the immunological responses. Although authors described the relationships between OGG1 and NF-kappaB, dysregulation of BER could simultaneously affect immune responses as well. If the main function of the OGG1 is upon the BER system, authors had better reconsider the biological consequences that come directly from DNA damage that are not mediated by OGG1.

Response: We appreciate the comment. We included a section between lines 152-156 on page 6, addressing this aspect; “Of note, it was reported that OG is able to modulate gene expression without the need for its repair [56]. Moreover, several innate immune cells are hypersensitive to DNA oxidation due to insufficient downstream BER activity, ultimately leading to apoptosis [57-59].”

Moreover, regarding the recognition of the G-quartet structures, which are known to be formed on the specific regions of chromosomes, including telomeres, authors might better note some experimentally shown evidence to conclude that OGG1 recognizes to bind to. Of course, how that was shown should be explained in detail.

Response: We thank the comment about the confusing sanction on OGG1 and G-quadruplex. We modified the last paragraph of section 2.1 (page 6) and introduced the concept of potential G-quadruplex forming sequences (PQS) for clarity as follows: “Burrows and co-workers proposed that formation of G-quadruplexes within potential G-quadruplex forming sequences (PQS) requires a series of destabilizing steps [69]. Oxidation of a 5’ G to form OG within the PQS and subsequent OG excision by OGG1 and formation of an AP site combine to destabilize local duplex formation, favoring folding into a G-quadruplex structure.”

Figure 3: Number of human chromosomes should be indicated for each gene. Authors should add explanations for better understanding of the Figure. For example, what is the TF network? In the present form, I think readers cannot understand at all. As I wrote above, Figures but with minimum legend to be understood by themselves should be made, without a need to read the text. That will surely shorten the text. Moreover, in Figure 3, the direction of the MUTYH gene from 5’- to 3’ is reversed compared to OGG1. Anyway, 5’-UTR/3’-UTR should be indicated for the MUTYH gene.

Response: We added the number of chromosomes in Figures 3 and 6 as suggested. Moreover, to avoid confusion with the concept of TF network, we changed it to Transcriptional factor controlling OGG1 and MUTYH. Finally, we specified the UTRs in both figures for clarity.

P9 – p11 (L239-340): Authors reviewed the OGG1 promoter and the epigenetic regulations. The sections 3.2.1 and 3.2.2 would better be just included in 3.2 as “OGG1 gene structure and regulation”.

Response: We thank this comment. In the revised manuscript, the referred sections are now 2.2, 2.2.1, and 2.2.2. We consider that combining these sections with section 2.2 would make it considerably longer. Moreover, we think that developing a section about the structure of the OGG1 promoter and epigenetics separately is necessary, given the importance of each section and the amount of experimental data available for the discussion.

Figure 5: In the legend, explanations for better understanding this Figure are required. For example, how was the ribbon model drawn? How was the OGG1 network obtained? The information should be given in the legend.

Response: In the revised version of the manuscript, figure 5 was split into figures 3 and 6, including OGG1 and MUTYH information, respectively. Now, in the figure capture, we included an explanation about how we made the figures and the PiP interaction networks.

Table 1: The title of the Table should be placed on the Top. Title should not be included in the Table itself. In short, the most upper line should be eliminated. Additionally, this Table needs to be separated into two, to make Table 1 and 2, for OGG1 and MUTYH, respectively. The newly made Tables need legends, and the text could be greatly reduced.

Response: In the revised version of the manuscript, we split table 1 into tables 1 and 2, containing OGG1 and MUTYH information, respectively. The format of the tables was not selected by us. We assume that it was formatted for the editorial team according to the journal requirements.

1. MUTYH (p19-29)

I advise authors themselves confirm Figures for MUTYH, which were separated from Figures 1 to 5, to be appropriately edited and placed in the appropriate places in this section.

Response: Addressed as suggested, except for figure 1. The explanation for keeping figure 1 given above as follows: “both OGG1 and MUTYH have complementary repair activities correcting OG:C and OG:A DNA lesions, thus, we think that showing a scheme with both OGG1- and MUTYH-mediated BER is appropriate, allowing to portray a full picture of the repair pathway. Therefore, we suggest leaving it as it is.”

Figure 6: This Figure and the related descriptions seem to be better moved to the Introduction section because it illustrates one of the biological functions that OGG1 and MUTYH are involved in.

Response: The referred figure is now figure 5, and we moved it next to the section where it is mentioned.

I felt that the description is heavily redundant to understand essential things. I strongly encourage authors to avoid redundant expressions but remain essential descriptions and that will improve this manuscript.

Response: We appreciate and totally understand this comment about redundancy. We hope that this revised version of the manuscript is found improved in terms of length and redundancy.

1. Concluding Remarks (p29)

As mentioned above, this section also needs to be shortened while remaining essential information. I advise authors to make the conclusion as an illustration or a cartoon with minimum sentences.

Response: We thank for the comment. We shortened the conclusion and included a couple of sentences to present unresolved issues faced in the field, as suggested by other reviewers: “Finally, there are still questions regarding the mechanisms these enzymes utilize. For example, understanding a general mechanism of product turnover may shed light on the implication of OG repair in telomeric instability and apoptosis. Additionally, understanding BERosome formation could present novel opportunities for therapeutic intervention.”

Minor comments

Generally, gene names should be typed in italic to avoid misunderstandings with protein names. I recommend authors confirm all gene names and Gene IDs at the NIH Gene (https:// www.ncbi.nlm.nih.gov/gene/). Authors might better recheck all through the text.

Page 3, L88: OGG1 and Mutyh as Part of the Human Go Repair Sys-Tem; OGG1 and MUTYH as Part of the Human GO Repair System

Response: Re-checked as suggested. We thank the suggestion. In figure 1, we changed the names of DNA ligase I and III to LIG1 and LIG3, respectively, as they are annotated in the UniProt database.

Page 29-41: I think References are not formatted as MDPI journal form. Authors had better format themselves. While doing so, corrections could be made as well.

Response: Revised.

 

 

 

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors solved my concerns. I have no issue with this manuscript.

Reviewer 2 Report

Comments and Suggestions for Authors

The revised manuscript of a review article, which was written by Dr. Ana P. Gómez-Ramírez et al, has been improved according to my suggestions. I confirmed all questions that I asked were appropriately addressed. Figures and Tables were surely made modifications or improvements, and they were placed on the right places. Herewith, I honestly evaluate that the manuscript can be accepted for publication as a review article in the journal, biomolecules.

Recommendation: Accept in present form