Identification and inhibition of the Cyclin D Rb-docking interface that drives cell division

Topacio, B. R.; Fleming, C.; Lanz, M.; Zhang, S.; Xie, S.; Tuvikene, J.; Weaver, A.; Sanidas, I.; Sage, J.; Rubin, S.; Koivomagi, M.; Skotheim, J.

doi:10.64898/2026.01.14.699544

bioRxiv · 10.64898/2026.01.14.699544

Identification and inhibition of the Cyclin D Rb-docking interface that drives cell division

Topacio, B. R.·Fleming, C.·Lanz, M.·Zhang, S.·Xie, S.·Tuvikene, J.·Weaver, A.·Sanidas, I.·Sage, J.·Rubin, S.·Koivomagi, M.·Skotheim, J.

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Abstract

The animal cell division cycle is initiated by the cyclin-dependent kinases CDK4 and CDK6 in complex with D-type cyclins. Cyclin D-CDK4/6 complex formation is promoted by the assembly factors p21 and p27, which bind both subunits. p27 binds the hydrophobic patch on cyclin D that is similar to the patch used by other cell cycle cyclins to dock their substrates. This raised the question as to how cyclin D could find its substrates if its hydrophobic patch were already occupied? Here, we show that D-type cyclins use their A2 helix to dock the retinoblastoma protein Rb, a key substrate regulating cell cycle progression. The specific interface of cyclin Ds A2 helix is unique among cyclins and its mutation slows proliferation. Taken together, our work identifies a cyclin D-substrate docking mechanism that can be targeted by novel cancer therapeutics.

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Topacio, B. R., Fleming, C., Lanz, M., Zhang, S., Xie, S., Tuvikene, J., Weaver, A., Sanidas, I., Sage, J., Rubin, S., Koivomagi, M., Skotheim, J.. 2026-01-15. Identification and inhibition of the Cyclin D Rb-docking interface that drives cell division. https://doi.org/10.64898/2026.01.14.699544

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