Histone Deacetylases and Their Potential as Targets to Enhance Tumour Radiosensitisation

Round 1

Reviewer 1 Report

The role of chromatin modification in DNA damage response and repair is extremely relevant and the potential of epigenetic drugs in tumour radiosensitisation is well established. This review, focused on histone deacetylases, is extremely informative and well organized and could be very useful for the radiobiologists’ audience. The text is clear and complete and includes most of the necessary references.

I have only a criticism:

In the introduction the Authors should give a clue on the mechanisms of direct involvement of histone acetylation/deacetylation in DNA repair. At least for some residues (H4K12 and K16 and H3K56) there are clear hypothesis. Some references need to be inserted:

1 – A recent and seminal paper by Clouaire et al. (2018) Comprehensive mapping of histone modifications and DNA double-strand breaks deciphers repair pathway chromatin signatures. Mol Cell 72, 250-262 needs to be discussed

2 – Some pioneering  work:

Bird AW et al., 2002 Acetylation of histone H4 by ESA1 is required for DSB break repair. Nature 419, 411-415

Murr R et al. 2006 Histone acetylation by TRAP-TIP60 modulates loading of repair proteins and repair of DNA DBS Natl Cell Biol 8, 91-99

Sharma GG et al., 2010 MOF and Histone H4 acetylation at lysine 16 are critical for DNA damage response and DSB repair. Mol Cell Biol 30, 3582-85

Author Response

Please see attachment.

Author Response File: Author Response.docx

Reviewer 2 Report

The review paper entitled: “Histone deacetylases and their potential as targets to enhance tumour radiosensitisation”, deals with an interesting topic of HDACs and their cellular functions, especially in DNA damage repair. The authors also demonstrate that HDAC inhibitors can effectively enhance tumour radiosensitisation, which therefore show potential for translation into the clinic for cancer patient benefit.
The development of HDAC inhibitors is a currently hot topic in the search for new anticancer drugs.

The authors described the histone deacetylases, their role in the cellular DDR and HDAC inhibitors in enhancing IR sensitivity. In the discussion section, the authors pointed out a valuable research gap that PBT should be examined for its ability to radiosensitise the cancer cells in combination with HDACi to define the mechanism of action which makes this work unique in comparison to the available reviews on this subject.

Overall the paper is well written and the bibliographies are updated, in my opinion, only a few minor changes are needed to improve the manuscript and to make it suitable for publication in Radiation.

The changes that need to be addressed by the authors are the following:

1. In Paragraph 1: Introduction the authors should better explain in lanes 66-68 how histone acetylation and deacetylation regulate DNA-DSBs.
2. In addition, in the lines from 78-81, the authors should better explain the differences in the formation of DNA damage regarding low and high LET radiation, eg. Radiation represented by high LET (examples)….forms clustered DNA lesions with higher complexity in comparison with low LET radiation…
3. Regarding Paragraph 2: Histone deacetylases, the authors described only the role of class I, II, and IV HDACs. The authors wrote that class III are not covered in this review. Considering the focus of this paragraph, the authors should better explain why class III HDACs are omitted or report SIRTS in the light of the bibliography on this topic as SIRTS are novel sensors for initiating DDR. SIRTs are highly important for DNA damage repair and genome stability.
4. As regards the role of HDAC10 in DNA damage repair (line 261), the authors should write exactly which mismatch genes.
5. In Paragraph 3 the authors wrote about the role of HDACs in the cellular DDR, I would recommend presenting a scheme containing a working model describing how HDAC and HDACi regulate DDR as a new Figure 2.
6. Regarding paragraph 4: HDAC inhibitors in enhancing IR radiosensitivity, the authors should add to each name of the drug other known drugs’ names, synonyms, and chemical class they are belonging to. Example (line 456): Romidepsin (FK228; FR901228) belonging to cyclic peptides is a …etc.

Author Response

Please see attachment.

Author Response File: Author Response.docx