Abstract
SAM domain and HD domain containing protein 1 (SAMHD1) is a deoxynucleotide triphosphohydrolase (dNTPase) that inhibits retroviruses by depleting intracellular deoxynucleotide triphosphates (dNTPs) in non-cycling myeloid cells. Although SAMHD1 is expressed ubiquitously throughout the human body, the molecular mechanisms regulating its enzymatic activity and function in non-immune cells are relatively unexplored. Here, we demonstrate that the dNTPase activity of SAMHD1 is regulated by acetylation, which promotes cell cycle progression in cancer cells. SAMHD1 is acetylated at residue lysine 405 (K405) in vitro and in vivo by an acetylatransferase, arrest defective protein 1 (ARD1). Acetylated SAMHD1 wildtype proteins have enhanced dNTPase activity in vitro, whereas non-acetylated arginine substituted mutants (K405R) do not. K405R mutant expressing cancer cells have reduced G1/S transition and slower proliferation compared to wildtype. SAMHD1 acetylation levels are strongest during the G1 phase, indicating a role during G1 phase. Collectively, these findings suggest that SAMHD1 acetylation enhances its dNTPase activity and promotes cancer cell proliferation. Therefore, SAMHD1 acetylation may be a potent therapeutic target for cancer treatment.
Highlights
Deoxyribonucleotide triphosphates are the precursors of DNA synthesis, and their strict balance is critical for proper DNA replication and repair in cells [1]
While screening for arrest defective protein 1 (ARD1)-binding proteins using affinity purification combined with mass spectrometry, we found that endogenous SAMHD1 binds to ARD1 in HEK293T cells (Supplementary Figure 1A)
The intensity of endogenous acetylated SAMHD1 was stronger in GFP-ARD1-overexpressing HEK293T cells, indicating that ARD1-mediated acetylation occurs in vivo (Figure 1C)
Summary
Deoxyribonucleotide triphosphates (dNTPs) are the precursors of DNA synthesis, and their strict balance is critical for proper DNA replication and repair in cells [1]. The availability of dNTP fluctuate: the largest pools are seen during S phase and the smallest in G0, which controls the initiation of DNA replication [2]. This fluctuation needs to remain within a range optimal for chromosomal replication in order to maintain genomic stability; eukaryotes use diverse mechanisms to strictly regulate the supply of dNTPs [3]. Because SAMHD1 can control the availability of dNTPs and cell cycle progression, it is likely associated with cancer; little has been investigated about its role in cancer proliferation
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
