Table 2.
Examples of mutator and carcinogenic potential of POLE and POLD1 exo domain mutations in humans and in model systems.
| Pol Amino Acid Change; (Exo Activity) § | Pol Region, Sequence, Conservation. Changed Amino Acids Are Underlined. Amino Acids Different from Human Protein Are Highlighted Grey. | Recurrently Found in Cancers *; Predominant Types of Cancer [124,139] and cBioPortal | Mutation Burden in Genomes of Tumors with the Change ** | Sporadic (s) or Hereditary (h) | Yeast Variants: | Mice Variants: | ||
|---|---|---|---|---|---|---|---|---|
| Allele Name; Amino Acid Change; (Exo Activity) | Mutator Effect Relative to Wild-Type; (Method of Determination) | Allele Variant (Exo Activity) | Mutator Effects Relative to Wild-Type; (Method of Determination); Cancer Incidence; Predominant Types of Cancer | |||||
| POLE | ||||||||
| D275A; E277A; (-) [122,140] |
Exo I Hs PVVLAFDIETTKLP Mm PVVLAFDIETTKLP Sc PVVMAFDIETTKPP | not found, classic model exo− variant | n/a | n/a |
pol2–4; D290A;E292A; (-) [125] |
5; (Canr) [20] 2.9; (Canr) [126] 4; (SNVs /genome) [141] ~11; (Lyp-) [141] |
PoleD272A;E274A/D272,E274A(-) *** | 10; (derivatives of BigBlueTM mice); [138] >70; (ouabain resistance) or 170; thioguanine resistance in MEFs) [138] ;medium; intestine adenocarcinoma, nodal lymphoma [138] |
| D275V; (-) ***D275A; (-) |
Exo I Hs PVVLAFDIETTKLP Mm PVVLAFDIETTKLP Sc PVVMAFDIETTKPP | +; endometrial, breast, glioblastoma, colorectal, lung |
med | s |
pol2-D290V;
(-) |
2.3; (Canr) [133] ~9; (Lyp-) [141] |
||
| P286R; (−/+) [122] |
Exo I Hs FDIETTKLPLKFPD Mm FDIETTKLPLKFPD Sc FDIETTKPPLKFPD | +++; colon, endometrial, ovarian, high grade glyoma pancreatic, breast, prostate, bladder and other cancers |
ultra-high | s | P301R; (-/+) [125] |
150; (Canr) [126]~200; (Lyp-) [141] 63; (SNVs/ genome) [141] |
PoleP286R/+ (P286R; nd |
~40; (NGS #) [135] >100; (NGS) [122]; high; thymic lymphomas, lung adenocarcinomas, angiosarcoma [135]; thymic lymphomas, splenic lymphomas [122] |
| P286H; (−/+) [122,142] P286L |
Same region, but different amino acid change | +; colon, glioblastoma, stomach |
ultra-high | s | P301H; nd |
13; (Canr) [133] |
||
| S459F; (-) [122,142] |
ExoIII Hs TYSVSDAVATYY Mm TYSVSDAVATYY Sc EYSVSDAVATYY | ++; colon, endometrial, glioblastoma, duodenal |
high | s | S474F; nd |
30; (Canr) [133] |
PoleS459F/S459F (S459F); nd |
>220; (NGS); high; thymic/splenic lymphomas [122] |
| F367S; (+/−) [122,142] |
Exo II Hs MVTYNGDFFDWPF Mm MVTYNGDFFDWPF Sc ISTFNGDFFDWPF | +; endometrial, colon |
ultra-high | s | F382S; nd |
17; (Canr) [133] |
||
| P436R; nd |
Exo V Hs AKLGYDPVELDP Mm AKLGYDPVELDP Sc AKLGYNPIELDP | +; endometrial, colorectal |
ultra-high | s | P451R; nd |
5.2; (Canr) [133] |
||
| V411L; (+/-) [142] |
Hs CLRWVKRDSYLPV Mm CLRWVKRDSYLPV Sc CFRWVKRDSYLPQ | +++; +; endometrial, colorectal, glioblastoma, kidney cancer, ovarian medulloblastoma, urinary tract, cervix, stomach |
ultra-high | s h |
V426L; nd |
1.2; (Canr) [133] ~5; (Lyp-) [141] 1.8; (SNVs/ genome) [141] |
||
| L424V; (+/-) [122,142] |
Exo IV Hs LPVGSHNLKAAAK Mm LPVGSHNLKAAAK Sc LPQGSQGLKAVTQ | +; +++; colorectal, endometrial, lung, breast, glyoblastoma, duodenal [122] |
med | s h |
L439V; nd |
5.2; (Canr) [133] ~33; (Lyp-) [141] 7; (SNVs/ genome) [141] |
||
| POLD1 | ||||||||
| D316A; E318A; (-) |
Exo I Hs LRVLSFDIECAGRK Mm LRVLSFDIECAGRK Sc LRIMSFDIECAGRI | Double change not found, but +; D316N or D316G; endometrial |
high | s |
pol3–01; D321A;E323A; (+) [22] |
130; (FOAr) [21] 110; (Canr) [22] |
||
| D402A; (-) [143] |
ExoII Hs TGYNIQNFDLPYLI Mm TGYNIQNFDLPYLI Sc TGYNTTNFDIPYLL | not found in cBio, but other changes of the nearby amino acids in motif +; breast adeno carcinoma, melanoma |
Q399H med P404Shigh |
s |
pol3–4DA; D407A; (-) [144] pol3–4DV; D407V;nd |
55; (Canr) [22] 76; (Canr) [22] |
Pold1D400A/D400A (-)[145] |
3; (derivatives of BigBlueTM mice) [138] ;>10; (ouabain resistance in MEFs) [145] 6; (fibrosarcoma cell line) [145] >50; (ouabain or thioguanine resistance in MEFs) [138] ;high; thymic lymphomas, tail skin carcinoma, lung adenocarcinoma |
| D515A; (-) [146] |
Exo III Hs AVYCLKDAYLPLRL Mm AVYCLKDAFLPLRL Sc AVYCLKDAYLPLRL | +; currently not found, but D515N variant was detected in melanoma |
med | s |
pol3–5DV; D520V; (-) [22] |
20; (Canr) [22] |
||
§ Exo activity: (-)—none; (−/+)- residual; (+/−)—detectable, around 50% of wild-type; (+)—more than 50% of wild-type *—Found in cancers: +—less than 10 times; ++—10–30; +++—more than 30. Sources of information: cBioPortal (http://www.cbioportal.org/) and [2,124]. **—Mutation load: med—<1000 per genome, high—1000–5000; ultra-high—more than 5000—methods of determination of mutation rate or frequency and reference: in vivo mutation in Big Blue mice [138]; 6-tioguanine or ouabain-resistant mutants in cultured embryonic fibroblasts, MEFs [138], #—NGS, mutations per megabase [135]; ***(-)—missing catalytic residue, predicted to be exo−.n/a—not applicable; nd—not determined.