Ovejero et al explore the role of DNA damage in DLBCL based on a published CRISPR-Cas9 screening. They identify CHEK1, WEE1, ATR and RAD51 as putative targets and show sensitivity after selective targets. They further show synergy with cyclophosphamide and doxorubicin. There are several mayor issues linked the data that would be required to be addressed as below:

• In the abstract and introduction, the authors should specify that they used CRISPR screening comes from prior work and report the reference. The current statement is misleading.
• The problem with the combination of doxorubicin with NU-7441 in second line is the dose limitation of doxorubicin for cardiotoxocity - the authors should comment on this
• In the methods, can the authors specify the DLBCL subtypes of the used cell lines (e.g., ABC, GCB, DH)?

• Page 14 PAGE 202, selecting genes for only DNA repair pathways is quite biased. The authors should provide first the unfiltered analysis which identifies the top up and downregulated gene targets. This will show whether DNA repair is an important mechanism of resistance. If this is the case, they can then justify their focused analysis on the DNA repair pathways.

• Page 14 line 206-225, all this section reports informations of prior studies using inhibitors of DNA damage. As such, it should be shorten and moved to the introduction as part of the background

• Page 15- line 237: What is the FANC score? The authors mentioned that they identified GEP-based DNA repair signatures, but they have never explained what is the FANC score and the reader is at lost
• Page 15- line 238: same as above for HRR and BER scores - what are these? What does this mean? It difficult to interpret their conclusions
• Page 15 line 243-244: Please town down this conclusion - their data may suggest (not demonstrate) the implication of DNA repair in treatment resistance of DLBCL.
• Page 16: Can the authors show WB of PARP cleavage and changes of the apoptosis proteins. Currently they only show bar graphs which are not enough, nor they are convincing.
• Page 17: What is the impact of combination on apoptosis and cell cycle? Can the authors show the changes by WB and flow cytometry.
• Page 18: It is not clear how the authors performed the experiment with primary cells. 1) How did the authors identified tumor cells? Not all the B cells are tumor cells. 2) what's the ratio of B cell and non-malingnant microenvironment? If they used different cells, did they change the ratio? 3) Which cells of the microenvironment were used? T cells? Macrophages? Neutrophils? Fibroblast? Each of them have a different sensitivity and lenght of time to remain alive. 4) How did they trace and calculate the proportion of tumor cells that they are alive/dead? How did they rule out the interference of microenvironment?

Minor
- The current methods are too long - they authors may consider to shorten them
- The quality of the figures should be implemented. Currently there are only bar graphs