Nucleotide excision repair genes shaping embryonic development

Nucleotide excision repair (NER) is a highly conserved mechanism to remove helix-distorting DNA lesions. A major substrate for NER is DNA damage caused by environmental genotoxins, most notably ultraviolet radiation. Xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy are three human disorders caused by inherited defects in NER. The symptoms and severity of these diseases vary dramatically, ranging from profound developmental delay to cancer predisposition and accelerated ageing. All three syndromes include developmental abnormalities, indicating an important role for optimal transcription and for NER in protecting against spontaneous DNA damage during embryonic development. Here, we review the current knowledge on genes that function in NER that also affect embryonic development, in particular the development of a fully functional nervous system.

Defects in ERCC1-XPF have major effects on energy balance. There are neurological defects in the hippocampus of these mice (and XPG deficient). Dietary restriction helps rescue the mice! This is an amazing and wonderful paper: Vermeij WP, Dolle ME, Reiling E, Jaarsma D, Payan-Gomez C, Bombardieri CR, Wu H, Roks AJ, Botter SM, van der Eerden BC et al. 3. For a review of this type it would be best to include some original insight about NER during development (that's the title …). For example, I recommend that the authors do some data mining on specific questions, and plot a few interesting graphs or tables.
Are the NER genes expressed differentially during development? In different tissues of an embryo? There is a lot of data out there. Can it help explain specifici neurological defects? Taking XPA as an example e.g. Developmental expression of genes, Allen Brain Atlas http://search.brain-map.org/search/index.html?query=%40entrez_id%2022590 http://mouse.brain-map.org/experiment/show?id=70474743 We are writing to inform you that the Editor has reached a decision on your manuscript RSOB-19-0166 entitled "Nucleotide Excision Repair during embryonic development", submitted to Open Biology.
As you will see from the reviewers' comments below, there are a number of criticisms that prevent us from accepting your manuscript at this stage. The reviewers suggest, however, that a revised version could be acceptable, if you are able to address their concerns. If you think that you can deal satisfactorily with the reviewer's suggestions, we would be pleased to consider a revised manuscript.
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When submitting your revised manuscript, please respond to the comments made by the referee(s) and upload a file "Response to Referees" in "Section 6 -File Upload". You can use this to document any changes you make to the original manuscript. In order to expedite the processing of the revised manuscript, please be as specific as possible in your response to the referee(s).
Please see our detailed instructions for revision requirements https://royalsociety.org/journals/authors/author-guidelines/ Once again, thank you for submitting your manuscript to Open Biology, we look forward to receiving your revision. If you have any questions at all, please do not hesitate to get in touch. This is a reasonable start on a review about a very interesting area, authored by two experts. I recommend that it is thoroughly revised and updated with focus on the following three points.

Sincerely
1. A major theme is not coming across clearly: many mammalian NER proteins have dual functions, and many of them are essential. I know that the authors understand this point well, but it is not coming across in the article. Only mild defects in some of the NER proteins can be tolerated. The developmental defects in XPB, XPD for example are most likely related to suboptimal transcription of some genes rather than NER defects. Similarly, ERCC1 and XPF are essential genes that function in SSA, the FA pathway, etc.
There is one figure (Fig 1) on NER, but it does not seem directly relevant to the theme of the review, "NER in development". At least one additional figure could be included to make the point of multifunctional proteins that affect overall transcription, or other repair pathways, as well as NER.
2. The citation list seems focused on the 1990s, early 2000's, and there has been quite a lot learned that could be useful here. For example, read through these and see how to incorporate into the thinking: Recent cryoEM structures of TFIIH in transcriptional mode and NER mode show how the proteins are disposed in these processes, where XPA binds, where nucleases cut, and suggest transition to the next steps in transcription & repair. Kokic

Do you have any ethical concerns with this paper? No
Comments to the Author This is an up-dated and thoughtful revision from two experts. It is certainly a major improvement on the original. I like the addition of Figure 2 and the Tables, this adds considerable interest. Some more comments for attention in improving the presentation are below: 1. Most important, statement on page 12 cannot be correct: "Hence, the two NER pathways, GG-NER and TC-NER, are probably necessary for proper embryonic development, from the oocyte to fully developed organismal stages." We know this is not right because XPA patients have zero NER, and their embryonic development is normal. Same for XPA mice, humans, flies, C. elegans etc. No fitness decrease or decrease in litter size. (see also author's Table 2) The XPA-associated deficits come in the form of accelerated neurological deterioration later in life.
Later in the article, the discussion is good and more nuanced, complete and scholarly with respect to other genes with dual functions in NER and other processes. See also discussion in "DNA Repair and Mutagenesis" 2nd edition book.
3. XPV, I recommend that instead of citing only the Hanaoka 1999 lab reference, a review for XPV -pol eta mutations to avoid omitting the Prakash papers and other related info, see ref 13 Lehmann et al that I used in News and Views, or something similar https://www.nature.com/articles/d41586-018-05255-1 4. Page 7, "many of these phenotypes may be due to the severely mutagenic and chromosome-destabilizing consequences of a stalled RNAP2 and a failure to accomplish TC-NER (40, 41)." I recommend that you also include the possibility that some of the neurological phenotypes might arise from a transcriptional defect. 5. Page 9 and elsewhere: note that CS and TTD patients do not show an increased incidence of cancers. Only XP. 6. Page 9, hydrogen peroxide and superoxide do not react much if at all with DNA. They generate hydroxyl radicals (.OH) via an iron-catalyzed Fenton reaction which are highly reactive and then damage DNA.

27-Sep-2019
Dear Dr Araújo We are pleased to inform you that your manuscript RSOB-19-0166.R1 entitled "Nucleotide Excision Repair and its players during embryonic development" has been accepted by the Editor for publication in Open Biology. The reviewer(s) have recommended publication, but also suggest some minor revisions to your manuscript. Therefore, we invite you to respond to the reviewer(s)' comments and revise your manuscript.
Please submit the revised version of your manuscript within 14 days. If you do not think you will be able to meet this date please let us know immediately and we can extend this deadline for you.
To revise your manuscript, log into https://mc.manuscriptcentral.com/rsob and enter your Author Centre, where you will find your manuscript title listed under "Manuscripts with Decisions." Under "Actions," click on "Create a Revision." Your manuscript number has been appended to denote a revision.
You will be unable to make your revisions on the originally submitted version of the manuscript. Instead, please revise your manuscript and upload a new version through your Author Centre.
When submitting your revised manuscript, you will be able to respond to the comments made by the referee(s) and upload a file "Response to Referees" in "Section 6 -File Upload". You can use this to document any changes you make to the original manuscript. In order to expedite the processing of the revised manuscript, please be as specific as possible in your response to the referee(s). Please see our detailed instructions for revision requirements https://royalsociety.org/journals/authors/author-guidelines/.
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Reviewer(s)' Comments to Author:
Referee: 1 Comments to the Author(s) This is an up-dated and thoughtful revision from two experts. It is certainly a major improvement on the original. I like the addition of Figure 2 and the Tables, this adds considerable interest. Some more comments for attention in improving the presentation are below: 1. Most important, statement on page 12 cannot be correct: "Hence, the two NER pathways, GG-NER and TC-NER, are probably necessary for proper embryonic development, from the oocyte to fully developed organismal stages." We know this is not right because XPA patients have zero NER, and their embryonic development is normal. Same for XPA mice, humans, flies, C. elegans etc. No fitness decrease or decrease in litter size. (see also author's Table 2) The XPA-associated deficits come in the form of accelerated neurological deterioration later in life.
Later in the article, the discussion is good and more nuanced, complete and scholarly with respect to other genes with dual functions in NER and other processes. See also discussion in "DNA Repair and Mutagenesis" 2nd edition book.
3. XPV, I recommend that instead of citing only the Hanaoka 1999 lab reference, a review for XPV -pol eta mutations to avoid omitting the Prakash papers and other related info, see ref 13 Lehmann et al that I used in News and Views, or something similar https://www.nature.com/articles/d41586-018-05255-1 4. Page 7, "many of these phenotypes may be due to the severely mutagenic and chromosome-destabilizing consequences of a stalled RNAP2 and a failure to accomplish 41)." I recommend that you also include the possibility that some of the neurological phenotypes might arise from a transcriptional defect. 5. Page 9 and elsewhere: note that CS and TTD patients do not show an increased incidence of cancers. Only XP. We are pleased to inform you that your manuscript entitled "Nucleotide Excision Repair genes shaping embryonic development" has been accepted by the Editor for publication in Open Biology.
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Nucleotide Excision Repair and its players during embryonic development
Dear Prof. David Glover, Thank you for your letter and for the opportunity of submitting a new revised version of our manuscript.
We are now resubmitting a substantially revised and improved manuscript. We have updated our bibliography and provide new data-mining analysis, new figure panels and tables. In addition, we have changed many parts of the text and also our title in order to be more clear about the information revised.
Below, we include a response to the reviewers' comments in bold dark blue.
We hope you will find that our answers have satisfactorily addressed your concerns and that you will consider that the new manuscript is appropriate for publication in Open Biology.

Referee #1 Araújo and Kuraoka
This is a reasonable start on a review about a very interesting area, authored by two experts. I recommend that it is thoroughly revised and updated with focus on the following three points. 1. A major theme is not coming across clearly: many mammalian NER proteins have dual functions, and many of them are essential. I know that the authors understand this point well, but it is not coming across in the article. Only mild defects in some of the NER proteins can be tolerated. The developmental defects in XPB, XPD for example are most likely related to suboptimal transcription of some genes rather than NER defects. Similarly, ERCC1 and XPF are essential genes that function in SSA, the FA pathway, etc.
There is one figure (Fig 1) on NER, but it does not seem directly relevant to the theme of the review, "NER in development". At least one additional figure could be included to make the point of multifunctional proteins that affect overall transcription, or other repair pathways, as well as NER.
We have completed figure 1 with more details of the involvement of NER factors in replication, transcription and other repair pathways, which might also influence development.
2. The citation list seems focused on the 1990s, early 2000's, and there has been quite a lot learned that could be useful here. For example, read through these and see how to incorporate into the thinking: