Replication Bypass of the N-(2-Deoxy-d-erythro-pentofuranosyl)-urea DNA Lesion by Human DNA Polymerase η
Urea lesions in DNA arise from thymine glycol (Tg) or 8-oxo-dG; their genotoxicity is thought to arise in part due to their potential to accommodate the insertion of all four dNTPs during error-prone replication. Replication bypass with human DNA polymerase η (hPol η) confirmed that all four dNTPs were inserted opposite urea lesions but with purines exhibiting greater incorporation efficiency. X-ray crystal structures of ternary replication bypass complexes in the presence of Mg2+ ions with incoming dNTP analogs dAMPnPP, dCMPnPP, dGMPnPP, and dTMPnPP bound opposite urea lesions (hPol η·DNA·dNMPnPP complexes) revealed all were accommodated by hPol η. In each, the Watson-Crick face of the dNMPnPP was paired with the urea lesion, exploiting the ability of the amine and carbonyl groups of the urea to act as H-bond donors or acceptors, respectively. With incoming dAMPnPP or dGMPnPP, the distance between the imino nitrogen of urea and the N9 atoms of incoming dNMPnPP approximated the canonical distance of 9 Å in B-DNA. With incoming dCMPnPP or dTMPnPP, the corresponding distance of about 7 Å was less ideal. Improved base-stacking interactions were also observed with incoming purines vs pyrimidines. Nevertheless, in each instance, the α-phosphate of incoming dNMPnPPs was close to the 3'-hydroxyl group of the primer terminus, consistent with the catalysis of nucleotidyl transfer and the observation that all four nucleotides could be inserted opposite urea lesions. Preferential insertion of purines by hPol η may explain, in part, why the urea-directed spectrum of mutations arising from Tg vs 8-oxo-dG lesions differs.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:63 |
|---|---|
| Enthalten in: |
Biochemistry - 63(2024), 6 vom: 19. März, Seite 754-766 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Tomar, Rachana [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
8-Hydroxy-2'-Deoxyguanosine |
|---|
| Anmerkungen: |
Date Completed 20.03.2024 Date Revised 23.03.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1021/acs.biochem.3c00569 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM369029399 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM369029399 | ||
| 003 | DE-627 | ||
| 005 | 20240323235153.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240229s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1021/acs.biochem.3c00569 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1342.xml |
| 035 | |a (DE-627)NLM369029399 | ||
| 035 | |a (NLM)38413007 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Tomar, Rachana |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Replication Bypass of the N-(2-Deoxy-d-erythro-pentofuranosyl)-urea DNA Lesion by Human DNA Polymerase η |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 20.03.2024 | ||
| 500 | |a Date Revised 23.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Urea lesions in DNA arise from thymine glycol (Tg) or 8-oxo-dG; their genotoxicity is thought to arise in part due to their potential to accommodate the insertion of all four dNTPs during error-prone replication. Replication bypass with human DNA polymerase η (hPol η) confirmed that all four dNTPs were inserted opposite urea lesions but with purines exhibiting greater incorporation efficiency. X-ray crystal structures of ternary replication bypass complexes in the presence of Mg2+ ions with incoming dNTP analogs dAMPnPP, dCMPnPP, dGMPnPP, and dTMPnPP bound opposite urea lesions (hPol η·DNA·dNMPnPP complexes) revealed all were accommodated by hPol η. In each, the Watson-Crick face of the dNMPnPP was paired with the urea lesion, exploiting the ability of the amine and carbonyl groups of the urea to act as H-bond donors or acceptors, respectively. With incoming dAMPnPP or dGMPnPP, the distance between the imino nitrogen of urea and the N9 atoms of incoming dNMPnPP approximated the canonical distance of 9 Å in B-DNA. With incoming dCMPnPP or dTMPnPP, the corresponding distance of about 7 Å was less ideal. Improved base-stacking interactions were also observed with incoming purines vs pyrimidines. Nevertheless, in each instance, the α-phosphate of incoming dNMPnPPs was close to the 3'-hydroxyl group of the primer terminus, consistent with the catalysis of nucleotidyl transfer and the observation that all four nucleotides could be inserted opposite urea lesions. Preferential insertion of purines by hPol η may explain, in part, why the urea-directed spectrum of mutations arising from Tg vs 8-oxo-dG lesions differs | ||
| 650 | 4 | |a Journal Article | |
| 650 | 7 | |a Rad30 protein |2 NLM | |
| 650 | 7 | |a EC 2.7.7.7 |2 NLM | |
| 650 | 7 | |a 8-Hydroxy-2'-Deoxyguanosine |2 NLM | |
| 650 | 7 | |a 88847-89-6 |2 NLM | |
| 650 | 7 | |a DNA-Directed DNA Polymerase |2 NLM | |
| 650 | 7 | |a EC 2.7.7.7 |2 NLM | |
| 650 | 7 | |a DNA |2 NLM | |
| 650 | 7 | |a 9007-49-2 |2 NLM | |
| 650 | 7 | |a Nucleotides |2 NLM | |
| 650 | 7 | |a DNA Adducts |2 NLM | |
| 700 | 1 | |a Li, Songlin |e verfasserin |4 aut | |
| 700 | 1 | |a Egli, Martin |e verfasserin |4 aut | |
| 700 | 1 | |a Stone, Michael P |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Biochemistry |d 1962 |g 63(2024), 6 vom: 19. März, Seite 754-766 |w (DE-627)NLM000000469 |x 1520-4995 |7 nnns |
| 773 | 1 | 8 | |g volume:63 |g year:2024 |g number:6 |g day:19 |g month:03 |g pages:754-766 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1021/acs.biochem.3c00569 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 63 |j 2024 |e 6 |b 19 |c 03 |h 754-766 | ||