Alterations in cellular metabolism triggered by URA7 or GLN3 inactivation cause imbalanced dNTP pools and increased mutagenesis
Eukaryotic DNA replication fidelity relies on the concerted action of DNA polymerase nucleotide selectivity, proofreading activity, and DNA mismatch repair (MMR). Nucleotide selectivity and proofreading are affected by the balance and concentration of deoxyribonucleotide (dNTP) pools, which are stri...
Gespeichert in:
| Hauptverfasser: | , , |
|---|---|
| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
2017
|
| In: |
Proceedings of the National Academy of Sciences of the United States of America
Year: 2017, Jahrgang: 114, Heft: 22, Pages: E4442-E4451 |
| ISSN: | 1091-6490 |
| DOI: | 10.1073/pnas.1618714114 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: http://dx.doi.org/10.1073/pnas.1618714114 Verlag, kostenfrei, Volltext: http://www.pnas.org/content/114/22/E4442 
|
| Verfasserangaben: | Tobias T. Schmidt, Gloria Reyes, Kerstin Gries, Cemile Ümran Ceylan, Sushma Sharma, Matthias Meurer, Michael Knop, Andrei Chabes, and Hans Hombauer |
MARC
| LEADER | 00000caa a2200000 c 4500 | ||
|---|---|---|---|
| 001 | 1561719072 | ||
| 003 | DE-627 | ||
| 005 | 20220813205208.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 170804s2017 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1073/pnas.1618714114 |2 doi | |
| 035 | |a (DE-627)1561719072 | ||
| 035 | |a (DE-576)491719078 | ||
| 035 | |a (DE-599)BSZ491719078 | ||
| 035 | |a (OCoLC)1340977939 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rda | ||
| 041 | |a eng | ||
| 084 | |a 32 |2 sdnb | ||
| 100 | 1 | |a Schmidt, Tobias Thomas |e VerfasserIn |0 (DE-588)1137714158 |0 (DE-627)895078368 |0 (DE-576)491718713 |4 aut | |
| 245 | 1 | 0 | |a Alterations in cellular metabolism triggered by URA7 or GLN3 inactivation cause imbalanced dNTP pools and increased mutagenesis |c Tobias T. Schmidt, Gloria Reyes, Kerstin Gries, Cemile Ümran Ceylan, Sushma Sharma, Matthias Meurer, Michael Knop, Andrei Chabes, and Hans Hombauer |
| 264 | 1 | |c 2017 | |
| 300 | |a 10 | ||
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Gesehen am 04.08.2017 | ||
| 520 | |a Eukaryotic DNA replication fidelity relies on the concerted action of DNA polymerase nucleotide selectivity, proofreading activity, and DNA mismatch repair (MMR). Nucleotide selectivity and proofreading are affected by the balance and concentration of deoxyribonucleotide (dNTP) pools, which are strictly regulated by ribonucleotide reductase (RNR). Mutations preventing DNA polymerase proofreading activity or MMR function cause mutator phenotypes and consequently increased cancer susceptibility. To identify genes not previously linked to high-fidelity DNA replication, we conducted a genome-wide screen in Saccharomyces cerevisiae using DNA polymerase active-site mutants as a “sensitized mutator background.” Among the genes identified in our screen, three metabolism-related genes (GLN3, URA7, and SHM2) have not been previously associated to the suppression of mutations. Loss of either the transcription factor Gln3 or inactivation of the CTP synthetase Ura7 both resulted in the activation of the DNA damage response and imbalanced dNTP pools. Importantly, these dNTP imbalances are strongly mutagenic in genetic backgrounds where DNA polymerase function or MMR activity is partially compromised. Previous reports have shown that dNTP pool imbalances can be caused by mutations altering the allosteric regulation of enzymes involved in dNTP biosynthesis (e.g., RNR or dCMP deaminase). Here, we provide evidence that mutations affecting genes involved in RNR substrate production can cause dNTP imbalances, which cannot be compensated by RNR or other enzymatic activities. Moreover, Gln3 inactivation links nutrient deprivation to increased mutagenesis. Our results suggest that similar genetic interactions could drive mutator phenotypes in cancer cells. | ||
| 650 | 4 | |a CTP biosynthesis | |
| 650 | 4 | |a DNA polymerases | |
| 650 | 4 | |a DNA replication fidelity | |
| 650 | 4 | |a dNTP pool imbalance | |
| 650 | 4 | |a mismatch repair | |
| 700 | 1 | |a Meurer, Matthias |e VerfasserIn |0 (DE-588)1064186963 |0 (DE-627)813075610 |0 (DE-576)423831542 |4 aut | |
| 700 | 1 | |a Knop, Michael |e VerfasserIn |0 (DE-588)1064187552 |0 (DE-627)813076749 |0 (DE-576)423832107 |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |a National Academy of Sciences (Washington, DC) |t Proceedings of the National Academy of Sciences of the United States of America |d Washington, DC : National Acad. of Sciences, 1915 |g 114(2017), 22, Seite E4442-E4451 |h Online-Ressource |w (DE-627)254235379 |w (DE-600)1461794-8 |w (DE-576)073260509 |x 1091-6490 |7 nnas |
| 773 | 1 | 8 | |g volume:114 |g year:2017 |g number:22 |g pages:E4442-E4451 |g extent:10 |a Alterations in cellular metabolism triggered by URA7 or GLN3 inactivation cause imbalanced dNTP pools and increased mutagenesis |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1073/pnas.1618714114 |x Verlag |x Resolving-System |z kostenfrei |3 Volltext |
| 856 | 4 | 0 | |u http://www.pnas.org/content/114/22/E4442 |x Verlag |z kostenfrei |3 Volltext |
| 951 | |a AR | ||
| 992 | |a 20170804 | ||
| 993 | |a Article | ||
| 994 | |a 2017 | ||
| 998 | |g 1064187552 |a Knop, Michael |m 1064187552:Knop, Michael |d 700000 |d 706000 |d 700000 |d 718000 |e 700000PK1064187552 |e 706000PK1064187552 |e 700000PK1064187552 |e 718000PK1064187552 |k 0/700000/ |k 1/700000/706000/ |k 0/700000/ |k 1/700000/718000/ |p 7 | ||
| 998 | |g 1064186963 |a Meurer, Matthias |m 1064186963:Meurer, Matthias |d 700000 |d 706000 |e 700000PM1064186963 |e 706000PM1064186963 |k 0/700000/ |k 1/700000/706000/ |p 6 | ||
| 999 | |a KXP-PPN1561719072 |e 297627861X | ||
| BIB | |a Y | ||
| SER | |a journal | ||
| JSO | |a {"relHost":[{"id":{"issn":["1091-6490"],"zdb":["1461794-8"],"eki":["254235379"]},"language":["eng"],"type":{"bibl":"periodical","media":"Online-Ressource"},"corporate":[{"display":"National Academy of Sciences","role":"aut"}],"disp":"National Academy of Sciences (Washington, DC)Proceedings of the National Academy of Sciences of the United States of America","pubHistory":["1.1915 -"],"recId":"254235379","note":["Gesehen am 09.03.2022"],"origin":[{"dateIssuedDisp":"1915-","publisherPlace":"Washington, DC","publisher":"National Acad. of Sciences","dateIssuedKey":"1915"}],"part":{"text":"114(2017), 22, Seite E4442-E4451","pages":"E4442-E4451","volume":"114","issue":"22","extent":"10","year":"2017"},"titleAlt":[{"title":"PNAS online"},{"title":"PNAS"}],"title":[{"title_sort":"Proceedings of the National Academy of Sciences of the United States of America","title":"Proceedings of the National Academy of Sciences of the United States of America"}],"physDesc":[{"extent":"Online-Ressource"}]}],"title":[{"title_sort":"Alterations in cellular metabolism triggered by URA7 or GLN3 inactivation cause imbalanced dNTP pools and increased mutagenesis","title":"Alterations in cellular metabolism triggered by URA7 or GLN3 inactivation cause imbalanced dNTP pools and increased mutagenesis"}],"person":[{"given":"Tobias Thomas","display":"Schmidt, Tobias Thomas","family":"Schmidt","role":"aut"},{"given":"Matthias","display":"Meurer, Matthias","family":"Meurer","role":"aut"},{"role":"aut","family":"Knop","display":"Knop, Michael","given":"Michael"}],"physDesc":[{"extent":"10 S."}],"language":["eng"],"id":{"doi":["10.1073/pnas.1618714114"],"eki":["1561719072"]},"type":{"media":"Online-Ressource","bibl":"article-journal"},"origin":[{"dateIssuedDisp":"2017","dateIssuedKey":"2017"}],"note":["Gesehen am 04.08.2017"],"recId":"1561719072","name":{"displayForm":["Tobias T. Schmidt, Gloria Reyes, Kerstin Gries, Cemile Ümran Ceylan, Sushma Sharma, Matthias Meurer, Michael Knop, Andrei Chabes, and Hans Hombauer"]}} | ||
| SRT | |a SCHMIDTTOBALTERATION2017 | ||