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Imbalanced dNTP poo...
Imbalanced dNTP pools induce mutator and cancer phenotypes in mice
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- Tran, Phong (författare)
- Umeå universitet,Institutionen för medicinsk kemi och biofysik,Andrei Chabes
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- Moskalenko, Roman (författare)
- Umeå universitet,Institutionen för medicinsk kemi och biofysik
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- Sharma, Sushma (författare)
- Umeå universitet,Institutionen för medicinsk kemi och biofysik,Molekylär Infektionsmedicin, Sverige (MIMS)
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visa fler...
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- Nilsson, Anna Karin (författare)
- Umeå universitet,Institutionen för medicinsk kemi och biofysik
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- Watt, Danielle L. (författare)
- Umeå universitet,Institutionen för medicinsk kemi och biofysik
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- Andersson, Pernilla (författare)
- Umeå universitet,Patologi
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- Bergh, Anders (författare)
- Umeå universitet,Patologi
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- Chabes, Andrei, Professor (författare)
- Umeå universitet,Institutionen för medicinsk kemi och biofysik,Molekylär Infektionsmedicin, Sverige (MIMS)
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visa färre...
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(creator_code:org_t)
- Engelska.
- Relaterad länk:
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https://urn.kb.se/re...
Abstract
Ämnesord
Stäng
- The high accuracy of DNA replication is achieved through the nucleotide selectivity of DNA polymerases, polymerase proofreading, and the mismatch repair (MMR) system that act in series. While defects in proofreading and MMR are strongly associated with the development of cancers, decreased nucleotide selectivity due to mutations in replicative DNA polymerases is an uncommon driver of cancer development. Because nucleotide selectivity can also be decreased by imbalanced dNTP pools, we investigated to what extent imbalanced dNTP pools can induce cancers. To this end we developed a mouse model with a mutation in the allosteric specificity site of ribonucleotide reductase, which is responsible for the balanced production of dNTPs. These mice had ~2-fold increased dCTP and dTTP levels and normal dATP and dGTP levels. Despite this mild dNTP pool imbalance, mutant mice had a higher incidence and an earlier onset of cancers, and these were different from the cancers that developed in wild-type controls. Because dNTP pool imbalances can be caused by defects in a plethora of genes, we propose that decreased nucleotide selectivity might be a major factor contributing to the development of spontaneous cancers.
Nyckelord
- dNTP imbalance
- ribonucleotide reductase
- RRM1
- cancer
- spontaneous mutation rate
- medicinsk biokemi
- Medical Biochemistry
Publikations- och innehållstyp
- vet (ämneskategori)
- ovr (ämneskategori)