1. Joint Public Review:

    Chen et al. identify LIN37, a member of the DREAM transcriptional repressor complex as a new regulatory factor in DNA double-strand break (DSB) end resection. The study commences with a CRISPR-Cas9 screen for chromatin associated RPA in quiescent pre-B cells that lack DNA ligase 4. In addition to the established anti-resection components 53BP1-Shieldin, findings that validates the screen, the authors identify the transcriptional repression complex LIN37-DREAM. This well executed study makes a number of compelling observations. Namely, that LIN37 limits end-resection only in quiescent cells, that it is not epistatic with 53BP1-Shieldin, and loss of Lin37 allows expression of hundreds of genes including genes involved in DSB end resection and homologous recombination. yielding Rad51 filament formation and HR. All phenotypes were recapitulated by a LIN37 mutant that that does not interact with DREAM. Moreover, generality is shown across human and mouse cell types using either Cas9 breaks or IR.

    The results presented in this manuscript are fascinating and should open a new avenue to study cell cycle dependent regulation of DSB repair. The combination of cell biological and end-seq approaches make a very convincing argument for this unanticipated finding. The conclusions drawn from this work are for the most part well-supported by the data, which are of high-quality, and the experiments are rigorously performed. What is unclear is whether these effects are direct or indirect, including whether other DREAM factors also participate in this end-resection suppression. It would also be nice to know the cellular consequences of dysregulated HR that occurs in quiescent LIN37-deficient cells.

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  2. Evaluation summary:

    This manuscript will be of interest for scientists interested in cell cycle, DNA repair, transcription and genome stability opening a new chapter in studies of cell cycle dependent regulation of DSB repair. Much of the prior work has focused on cell cycle-driven post-translational regulatory modification of DSB end resection, whereas the current work finds transcriptional programs are equally, if not more, important in controlling resection in G0. This could open possibilities for gene therapy in post-mitotic tissues. The data are of high quality and the conclusions drawn are supported by the experimental evidence.

    (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. The reviewers remained anonymous to the authors.)

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