Table 1.
Selection of amino-acid positions/mutations in SAMHD1 in various cancers or AGS
| Amino acid position | Described function/structural significance | Mutation | Associated disease | Functional consequence of mutation |
|---|---|---|---|---|
| H123 | Primary allosteric dGTP/GTP-binding site [49] | 120_123del | AGS [6] | Reduced LINE-1 restriction [99] |
| H123P | AGS [6, 43] | Subcellular localization affected, partially nuclear and cytosolic [37]; reduced LINE-1 restriction [99]; no oligomerization [37] | ||
| H123Y | Skin melanoma [ICGC] | |||
| V133 | V133I | Colon adenocarcinoma [26] | Reduced dNTPase activity [26] | |
| D137 | Primary allosteric dGTP/GTP-binding site [1, 100] | D137A | - | Loss of dNTPase activity and HIV-1 restriction [1, 101] |
| D137H | Uterine corpus endometrial carcinoma [ICGC] | |||
| D137N | Colon adenocarcinoma [ICGC] | |||
| Q142 | Primary allosteric dGTP/GTP-binding site [1, 100] | Q142A | - | Reduced dNTPase activity [1] |
| Q142X | Esophageal adenocarcinoma [ICGC] | |||
| R143 | Points from primary allosteric dGTP/GTP-binding site to the rear of the active site [50] | R143C | AGS [6, 43]; uterine corpus endometrial carcinoma [ICGC] | Subcellular localization affected, partially nuclear and cytosolic [37]; no oligomerization [37]; loss of HIV-1 restriction [50] |
| R143H | AGS [6, 43]; liver hepatocellular carcinoma [ICGC] | Subcellular localization affected, partially nuclear and cytosolic [37]; reduced LINE-1 restriction [99]; no oligomerization [37] | ||
| R143X | AGS [43] | |||
| R145 | Primary allosteric dGTP/GTP-binding site [1] | R145A | - | Loss of dNTPase activity [1, 50] |
| R145Q | AGS [6, 43]; CLL [15]; colon adenocarcinoma [ICGC] | Subcellular localization affected, partially nuclear and cytosolic [43]; reduced LINE-1 [99] and loss of HIV-1 restriction [50]; no oligomerization [37]; loss of dNTPase activity [1] | ||
| R145X | AGS [6, 43]; CLL [15]; pancreatic adenocarcinoma [ICGC]; uterine corpus endometrial carcinoma [ICGC] | Subcellular localization affected, partially nuclear and cytosolic [43] | ||
| R164 | Forms salt bridge with phosphate group of dNTP bound to active site [1, 101] | R164A | - | Loss of dNTPase activity [1, 50] |
| R164Q | Pancreatic adenocarcinoma [ICGC]; uterine corpus endometrial carcinoma [ICGC] | |||
| R164X | AGS [43] | Subcellular localization affected, partially nuclear and cytosolic [43] | ||
| H167 | Coordinates cation in active site [1, 101] | H167Y | AGS [43] | Subcellular localization affected, partially nuclear and cytosolic [37]; reduced LINE-1 and HIV-1 restriction [37, 99]; no oligomerization [37]; reduced/loss of dNTPase activity [37] |
| I201 | I201N | AGS [6, 43]; CLL [15] | Subcellular localization affected, mainly cytosolic [43] /partially nuclear and cytosolic [37]; reduced LINE-1 and HIV-1 restriction [37, 99]; reduced oligomerization [37]; reduced/loss of dNTPase activity [37] | |
| H206 | Coordinates cation in active site [1, 101] | H206A/D207A | - | Loss of dNTPase activity [1]; proficient in HR and DNA end resection [4] |
| H206R | CLL [15] | |||
| H206Y | Skin cutaneous melanoma [ICGC] | |||
| D207 | Coordinates cation in active site [1, 101] | H206A/D207A | - | Loss of dNTPase activity [1]; proficient in HR and DNA end resection [4] |
| D207Y | Colon adenocarcinoma [26] | |||
| G209 | G209C | Lung squamous cell carcinoma [ICGC] | ||
| G209S | AGS [6, 43] | Subcellular localization affected, partially nuclear and cytosolic [43]; reduced LINE-1 restriction [99], but restrictive against HIV-1 [37]; normal oligomerization and dNTPase activity [37] | ||
| F217 | F217C | AGS [43] | Subcellular localization affected, partially nuclear and cytosolic [37]; reduced HIV-1 restriction [37]; no oligomerization [37]; reduced/loss of dNTPase activity [37] | |
| F217X | AGS [43] | |||
| R226 | R226G | AGS [43] | Subcellular localization affected, partially nuclear and cytosolic [37]; reduced HIV-1 restriction [37]; strongly reduced oligomerization [37]; reduced/loss of dNTPase activity [37] | |
| R226H | Colon adenocarcinoma [26] | |||
| H233 | Forms salt bridge with phosphate group of dNTP bound to active site [1] | H233A | - | Reduced dNTPase activity [1]; loss of HIV-1 restriction [50] |
| H233Y | Liver hepatocellular carcinoma [ICGC] | |||
| M254 | M254I | CLL [44, 102, 103]; skin cutaneous melanoma [ICGC] | ||
| M254V | AGS [6, 43] | Subcellular localization affected, mainly cytosolic [43]/partially nuclear and cytosolic [37]; reduced LINE-1 and HIV-1 restriction [37, 99]; normal oligomerization [37]; reduced/loss of dNTPase activity [37] | ||
| R290 | R290C | CLL [15] | ||
| R290H | AGS [43]; solon adenocarcinoma [ICGC]; stomach adenocarcinoma [ICGC] | Subcellular localization affected, partially nuclear and cytosolic [37]; reduced LINE-1 restriction [99]; no oligomerization [37] | ||
| R290S | Liver hepatocellular carcinoma [ICGC] | |||
| R290X | CLL [44, 102] | |||
| R305 | R305A | Rectum adenocarcinoma [ICGC] | Loss of dNTPase activity and loss of ssDNA cleavage activity [45] | |
| D311 | Coordinates cation in active site [1] | D311A | - | Subcellular localization not affected, mainly nuclear [37]; reduced HIV-1 restriction [37]; normal oligomerization [37]; reduced/loss of dNTPase activity [1, 37] |
| D311E | Breast invasive carcinoma [ICGC] | |||
| R333 | Secondary allosteric dNTP-binding site [49, 101] | R333C | Uterine corpus endometrial carcinoma [ICGC] | |
| R333E | - | Reduced tetramer formation and dNTPase activity [101] | ||
| R333H | AGS [ICGC]; breast invasive carcinoma [ICGC]; pediatric brain tumor [ICGC]; uterine corpus endometrial carcinoma [ICGC] | |||
| R333S | Breast invasive carcinoma [ICGC] | |||
| A338 | A338T | Colon adenocarcinoma [26] | Reduced dNTPase activity [26] | |
| A338V | Colon adenocarcinoma [ICGC] | |||
| Y360 | ssDNA binding [55] | Y360H | CLL [103] | |
| H364 | Forms hydrogen bonds at dimer-dimer interface [53]; ssDNA binding [55] | H364K | - | Reduced tetramer formation and dNTPase activity [53] |
| H364Q | Liver hepatocellular carcinoma [ICGC] | |||
| H364Y | Lung adenocarcinoma [ICGC] | |||
| R366 | Interacts with dNTP bound to active site [101] | R366C | CLL [17] | |
| R366H | Colon adenocarcinoma [26] | Reduced dNTPase activity [26] | ||
| L369 | Located at tetramer interface [49] | L369S | AGS [6, 43] | Subcellular localization affected, partially nuclear and cytosolic [37, 43]; reduced HIV-1 restriction [37]; reduced oligomerization [37]; reduced/loss of dNTPase activity [37] |
| M385 | Primary allosteric dGTP/GTP-binding site [49] | M385V | AGS [6, 43] | Subcellular localization affected, partially nuclear and cytosolic [37]; reduced HIV-1 restriction [37]; no oligomerization [37]; reduced/loss of dNTPase activity [37] |
| R442 | R442X | AGS [6, 43]; uterine corpus endometrial carcinoma [ICGC] | Subcellular localization affected, partially nuclear and cytosolic [37, 43]; reduced LINE-1 and HIV-1 restriction [37, 99]; no oligomerization [37]; reduced/loss of dNTPase activity [37] | |
| I448 | I448T | AGS [43]; malignant lymphoma [ICGC] | Subcellular localization affected, partially nuclear and cytosolic [37]; reduced HIV-1 restriction [37]; reduced oligomerization [37]; reduced/loss of dNTPase activity [37] | |
| R451 | Primary allosteric dGTP/GTP-binding site [49, 101] | R451C | CLL [15]; skin melanoma [ICGC] | |
| R451E | - | Reduced tetramer formation and loss of dNTPase activity [101, 104] | ||
| R451H | CLL [16] | |||
| R451L | CLL [15] | |||
| R451P | Colon adenocarcinoma [26] | |||
| R451S | Liver hepatocellular carcinoma [ICGC] | |||
| K484 | Conserved residue, located on SAMHD1 surface [4] | K484T | Gastric cancer [4] | Reduced interaction with CtIP (leading to impaired DNA end resection after DNA damage), no influence on dNTPase activity [4] |
| D497 | D497Y | Colon adenocarcinoma [26] | No dNTPase activity [26] | |
| Y521 | ssDNA binding [55] | Y521C | CLL [16] | |
| Y521D | Myeloma [105] | |||
| F545 | ssDNA binding [55] | F545L | CLL [15] | |
| Q548 | Second shell residue between activator and active site [104] | Q548A | - | Subcellular localization affected, partially nuclear and cytosolic [37]; reduced HIV-1 restriction [37]; normal oligomerization and dNTPase activity [37, 104]; reduced binding to ssDNA and ssRNA, reduced ssDNA cleavage [45] |
| Q548X | AGS [6, 43] | Subcellular localization affected, partially nuclear and cytosolic [37, 43]; reduced LINE-1 and HIV-1 restriction [37, 99]; no oligomerization [37]; reduced/loss of dNTPase activity [37] |
Selection of most interesting mutations that either have reported known functional consequences or a known involvement of the respective amino acid in structural integrity/cellular functions