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  1. Evaluation Summary:

    Targeting DNA repair pathway provides a novel approach managing malignancies and emphasizing the necessity of discovering biomarkers which could select patients who will benefit. In this research the authors performed comprehensive bioinformatic analysis and identified EXOSC1 as the endogenous source of mutation, which was then validated for its role in damaging DNA and could sensitize kidney renal clear cell carcinoma cells to DNA repair inhibitor. This research is innovative for proposing EXOSC1 role in mutagenesis and could serve as the biomarker to discriminate potential patients who would benefit from DNA repair inhibitor treatment.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)

  2. Reviewer #2 (Public Review):

    The authors found EXOSC1 expression is significantly correlated with C>A transversions in coding strands in KIRC, and suggested EXOSC1 induces the mutations in VHL gene which contributes to KIRC patient prognosis. Indeed, the TCGA database indicated that KIRC patients with high EXOSC1 showed a poor prognosis, thus this finding suggested that EXOSC1 may be a potential therapeutic target for KIRC patients with high EXOSC1 expression in combination with PARP inhibitor. This work is interesting and novel. It is first report on EXOSC1 has exosome independent function to induce single strand DNA cleavage. Although the mechanism links ssDNA cleavage to C>A transversion has not been addressed in the manuscript, and VHL mutations induced by EXOSC1 have not yet characterized and tested in KIRC tumorigenesis and progression. However, the association of EXOSC1 expression with the C>A transversion is clear and association with patient prognosis is convincing. More importantly, the therapeutic potential of combination with PRAP inhibitor makes this study important.

  3. Reviewer #3 (Public Review):

    Targeting DNA repair pathways is a critical therapeutic strategy for cancers. However, the DNA repair inhibitors markedly benefit only a part of patients necessitates the development of new strategies. In this manuscript, Xiao et al. showed that exosome component 1 (EXOSC1) leads to DNA damages and sensitizes KIRC cells to parp inhibitor. Because that endogenous source of mutation (ESM) constantly assaults genomic DNA and likely sensitize cancer cells to the inhibitor, the authors first analyzed the statistical relationship between the expression of individual genes and the mutations for KIRC. Among the ESM candidates, EXOSC1 most significantly promoted DNA damages and mutations by cleaving single-stranded DNA. Their further analyses demonstrated that high EXOSC1 patients showed a poor prognosis, and EXOSC1 sensitized cancer cells to PARP inhibitor. The topic was relative interesting as the field of synthetic lethal has attracted more intense interest recently. The whole study was logically designed, and the amount of work completed by the authors is abundant to justify the conclusion.

  4. Reviewer #1 (Public Review):

    In this research the authors performed comprehensive genomic mutation analysis based on public database, together with that on one of the most common mutated VHL gene in KIRC and screened EXOSC1 as an endogenous source of mutation. After validation of its mutagenesis role and description of the preference for cleaving C sites in single-stranded DNA, in vitro and in vivo assay were performed to elucidate EXOSC1 damaging DNA and could sensitize KIRC to DNA repair inhibitor like PARPi. This study was innovative and rigorously designed to propose a relative novel molecule accounting for DNA damage and put forward that EXOSC1 could function as a potential biomarker for selecting potential subgroups which would benefit from PARP inhibitor, though clinical data validation lacks and requires further investigation. Experimental data were sufficient to hold back the conclusion and this article will be of significance to researchers or clinicians who were specified in DNA repair mechanism and corresponding therapy.