Quandt et al. show that cyclin I (CCNI) is able to bind ad activate CDK6 (but not CDK4). CDK6-cyclin I phosphorylates RB similarly to CDK6-cyclin D1, and this event leads to E2F-mediated gene expression and cancer cell proliferation.

Strengths
i. Good experiments showing protein association, although binding affinities are nor shown.
ii. High-throughput two-hybrid experiment already showed CCNI might interact with CDK6 (Luck K, 2020 – Seen on BioGrid). Article goes on to validate this result and describe the function of interaction.
iii. Information on CCNI is sparce and this article serves to expand on the knowledge gap regarding this atypical cyclin.

Weaknesses
iv. Structural analysis of CCNI: Mentioned in the text as part of suggestions of which residues might be interacting with which residues in CDK6. This part of the text references supplementary figure 5, which shows computational data on interface energy contribution. In figure 1G they show that “CCNI residue E103 might be interacting with might be interacting with a group of three positively charged residues in CDK6, R60, R144 and R168”. This is interesting, but there is no actual mutational evidence indicating mutation of these residues inhibits interaction. This statement is not revisited, thus seemingly an unnecessary addition to the paper, unless the experiments are performed and shown in this manuscript.
v. Tried to state CCNI is overexpressed in tumor cells, however supplementary figure 11 is not that convincing.

I have examined the revised manuscript and I don’t have any additional concerns.