Cyclin A2 – CDK regulates SAMHD1 phosphohydrolase domain [DNA and Chromosomes]

April 6th, 2015 by Yan, J., Hao, C., DeLucia, M., Swanson, S., Florens, L., Washburn, M. P., Ahn, J., Skowronski, J.

SAMHD1 is a nuclear deoxyribo-nucleoside triphosphate triphosphohydrolase that contributes to the control of cellular deoxyribonucleoside triphosphates (dNTP) pool sizes through dNTP hydrolysis and modulates innate immune response to viruses. Cyclin A2-CDK1/2 phosphorylates SAMHD1 at threonine T592 but how this modification controls SAMHD1 functions in proliferating cells is not known. Here we show that SAMHD1 levels remain relatively unchanged during cell division cycle in primary human T lymphocytes and in monocytic cell lines. Inactivation of the bipartite CyclinA2-CDK binding site in SAMHD1 C-terminus described herein, abolished SAMHD1 phosphorylation on T592 during S and G2 phases thus interfering with DNA replication and progression of cells through S phase. The effects exerted by T592 phosphorylation-defective SAMHD1 mutants were associated with activation of DNA damage checkpoint and depletion of dNTP concentrations to levels lower than those seen upon expression of wild type SAMHD1 protein. These disruptive effects were relieved by either mutation of the catalytic residues of the SAMHD1 phosphohydrolase domain, or by a T592 phosphomimetic mutation, thus linking T592 phosphorylation state to the control of SAMHD1 dNTPase activity. Our findings support a model in which phosphorylation of T592 by CyclinA2-CDK downmodulates, but does not inactivate, SAMHD1 dNTPase in S phase, thereby fine tuning SAMHD1 control of dNTP levels during DNA replication.