Interactions between the DNA Damage Response and the Telomere Complex in Carcinogenesis: A Hypothesis
Round 1
Reviewer 1 Report
In the review "Interactions between the DNA damage response and the telomere complex in carcinogenesis: a hypothesis", the authors discuss in great detail the connections between DNA damage regulator and pathways and teleomere maintenance and how they relate to cancer.
The review is written well and easy to understand.
It is quite extensive, the authors do a go job of included describing the connections between telomeres and several aspects of DNA repair and it's regulators.
One drawback of this manuscript is the length. One considerations by the authors is focus on a certain aspect of DNA instead of an all is aspects that they include.
Author Response
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Author Response File: 
Author Response.docx
Reviewer 2 Report
The author in the above review article presents a very detailed description of the interplay between DNA damage and telomere alteration that eventually can influence tumorigenesis. The review could further benefit from having a separate section or atleast a paragraph on Break-induced repair and its role in telomere maintenance in absence of telomerase and how that could also potentially influence cancer. And lastly, the schematic figures need a bit more attention as far as presentation is concerned.
Author Response
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Author Response File: Author Response.docx
Reviewer 3 Report
1. Overall, the review is too verbose and lengthy and loses focus on the main topic toward the end. Many sections are repetitive of the author’s previous review (reference 1). The manuscript is unorganized in some areas, along with several punctuation errors throughout that should have been reviewed and fixed before being submitted to a journal for review.
2. References are not in order and must be fixed. Reference 2 needs to be referenced in the text.
3. Line 27 (1 and references thereof) need to be removed. I’m assuming the author left their notes in the text—the same for line 39 and line 64.
4. Periods are missing from several sentences throughout the text.
5. Many of the studies referenced go into more than enough detail. The author should learn to describe and summarize the significant points of a specific study within a few sentences. For example, the study described by Gupta et al., lines 348-372 (reference 69) should be summarized, followed by the author’s commentary.
6. The text in lines 487-500 has no references.
7. Section 3.1 Replication Stress should be summarized. The same for Section 4.1
8. Section 5.2 The PI3K pathway and DDR (lines 924-1148) should be significantly edited because it loses focus on the main topic of the review. The text becomes a PI3K and DDR review and loses the reader about what the review is about.
9. Figure 1 has no figure legend, and the arrows are not lined up correctly.
10. Figure 2 has no figure legend and should be more descriptive.
11. The Future directions section is missing #1.
Author Response
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Author Response File: Author Response.docx
Round 2
Reviewer 3 Report
Reviewer: The author has failed to appropriately reply to the Reviewer’s comments. This manuscript is NOT suitable for publication.
Dear Sir
The first comment of reviewer 3 was a scare to me. How could I forget reference 2 of the manuscript? But reference 2 was in its place. I imagine he refers to the following paragraph which he assumes should have been referenced as 2 “….is the Beckwith-Wiedemann syndrome, a genetic disease of the telomerase reverse transcriptase (TERT)-TGFβ- Smad pathway which is associated with an 800-fold risk of developing childhood cancer in many different organs. Another is represented by the tumor model reported by Passegué et al in which JunB inactivation specifically expanded the number of long term hematopoietic stem cells (LT-HDCs) leading to myeloproliferative disease” which is referenced as 1. I think it must be referenced as 1 because the reader of my paper would appreciate best the significance of these papers in relation to my thesis if he reads what I surmised from these papers in ref 1 (my own)
Reviewer: The author does not seem to understand how to cite references in a manuscript submitted for publication in a scientific journal.
Comments 2 and 3:”lines 27, 39 and 64 should be directly removed: In such case the Introduction should be rewritten entirely or would make no sense. Certainly I think the text makes sense as it is
Reviewer: The author did not respond to my comment which is in bold below.
3. Line 27 (1 and references thereof) need to be removed. I’m assuming the author left their notes in the text—the same for line 39 and line 64.
4 Period are missing in several sentences: He may be right
Reviewer: This is not an acceptable response. The author is still missing several punctuation marks. The author should have the manuscript checked by someone other than themselves.
5. The author should learn to describe and summarize the significant points of a specific study. For instance Gupta (lines487-500
6.The text lines 487-500 has no references. This is true but the text is constantly mentioning “these authors” which refers to the authors mentioned at the beggining
7 Replication stress should be summarizedas well as section 4.1 and8 the PI3K pathway
9 and10 fig legends of Figs1 an d2 are lacking 11Future direction section is missing
My response to questions 5, 7 and 8 may be lumped together:
The hypothesis defended runs through many different areas of research and most readers will not be familiar with some of them. (metaphorically could be compared to what happens in criminology: you must follow the money in many diverse situations). Without going into some detail, the text would be incomprehensible to many readers. In the discussion about Mre11 (Gupta, etc) I have gone into great detail. It may be excessive but there is a hidden suggestion (into which I cannot go here) that pro B cell tumors induced by Artemis mutation could benefit from the absence of telomere erosion in Mre11 mutation more than more mature tumors
I have reduced somewhat discussion of section on Replication stress but again not much for the same reason. As for the PI3K section, this is such complex pathway that it is impossible to summarize it in fewer words. Otherwise it would be absolutely incomprehensible. Notice that I tried to dissect the proliferative stimulus of mTORC1 that entails HSC exit from the stem cell compartment (similar to the action of c-Myc on stem cells) from the differentiation mediated by Foxo. The authors that described the antitumor effect of Foxo did not realize the implication of their discovery: that the stem cell must transit to a further differentiation stage before undergoing transformation and acquire some of the features of stemness. In short, all these sections need an effort on the part of the reader and even the lightest reduction of information would make the text unintelligible. However I have eliminated a couple of lines (ref 128) that are not necessary and may distract the attention of the reader. In addition I have added a little sentence to stress that this pathway acts in a double direction: loosing stemness protection (exit from stem compartment, differentiation and production of NFkB that favors survival of cancer stem cells.
I have tried to condense all these sections but only slightly
Reviewer: The author’s response is not acceptable.
Of course, I will add Fig legends and revise punctuation
Reviewer: The author’s response is not acceptable. The author added figure legend titles but NO description was included. The author should look at other reviews (other than his own) to see how figure legends constructed.
Author Response
I have provided an answer together with the necessary modifications in the version I provided last sunday night.
