Pools and Pols: Mechanism of a mutator phenotype

Sohl, Christal D.; Ray, Sreerupa; Sweasy, Joann B.

doi:10.1073/pnas.1505169112

Cited by 9 publications

(8 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We have recently demonstrated that the introduction of the Pol e-M644G (a mutation that reduces the accuracy of Pol e) or Pol δ-R696W (a human colon cancerassociated mutation) into budding yeast cells results in replication stress, leading to the activation of the genome integrity checkpoint and concomitant elevation of dNTP pools (17)(18)(19). The checkpointdependent elevation of dNTP pools was to a large degree responsible for the dramatic elevation of the mutation rates in these polymerase-defective yeast strains.…”

Section: Discussionmentioning

confidence: 99%

“…An equimolar elevation in dNTP pools also decreases DNA replication fidelity, both in yeast and bacteria, presumably by suppressing the proofreading activity of replicative DNA polymerases and by stimulating lesion bypass by both replicative and translesion DNA polymerases (11)(12)(13)(14)(15)(16). Recently, we showed in yeast that even a small elevation of the dNTP pool dramatically decreases the replication fidelity of exonuclease-deficient DNA polymerase e (Pol e) and DNA polymerase δ (Pol δ) harboring the cancer-associated R696W mutation (17)(18)(19). Based on these observations, we hypothesized that decreased nucleotide selectivity caused by changes in the absolute or relative concentrations of dNTPs could be one of the reasons for the increased mutation rates in cancers.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance

Rentoft

Lindell

Tran

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

105

155

View full text Add to dashboard Cite

Even small variations in dNTP concentrations decrease DNA replication fidelity, and this observation prompted us to analyze genomic cancer data for mutations in enzymes involved in dNTP metabolism. We found that sterile alpha motif and histidine-aspartate domain-containing protein 1 (SAMHD1), a deoxyribonucleoside triphosphate triphosphohydrolase that decreases dNTP pools, is frequently mutated in colon cancers, that these mutations negatively affect SAMHD1 activity, and that several SAMHD1 mutations are found in tumors with defective mismatch repair. We show that minor changes in dNTP pools in combination with inactivated mismatch repair dramatically increase mutation rates. Determination of dNTP pools in mouse embryos revealed that inactivation of one SAMHD1 allele is sufficient to elevate dNTP pools. These observations suggest that heterozygous cancer-associated SAMHD1 mutations increase mutation rates in cancer cells.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance

Rentoft

Lindell

Tran

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

105

155

View full text Add to dashboard Cite

show abstract

“…Reactions were conducted with widely used high dNTP concentrations and with cellular dNTP concentrations 26 . Utilizing cellular concentrations is biologically relevant and important because dNTP pool balance and concentrations affect the accuracy of DNA polymerases 27 . Telomerase was similarly processive with both dNTP mixes, but product yield was lower with the cellular dNTP mix as observed in reactions with 32 P-α-dGTP (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Oxidative guanine base damage regulates human telomerase activity

Fouquerel

Lormand

Bose

et al. 2016

Nat Struct Mol Biol

151

168

View full text Add to dashboard Cite

Changes in telomere length are associated with degenerative diseases and cancer. Oxidative stress and DNA damage have been linked to both positive and negative alterations in telomere length and integrity. Here we examined how the common oxidative lesion 8-oxo-7,8-dihydro-2′-deoxyguanine (8-oxoG) regulates telomere elongation by telomerase. When present in the deoxynucleoside triphosphate pool as 8-oxodGTP, telomerase utilization of the oxidized nucleotide during telomere extension is mutagenic and terminates further elongation. Depletion of the enzyme that removes oxidized dNTPs, MTH1, increases telomere dysfunction and cell death in telomerase positive cancer cells harboring shortened telomeres. In contrast, a pre-existing 8-oxoG within the telomeric DNA sequence promotes telomerase activity by destabilizing G-quadruplex structure in the DNA. We show that the mechanism by which 8-oxoG arises in the telomere, either by insertion of oxidized nucleotides or by direct reaction with free radicals, dictates whether telomerase is inhibited or stimulated and thereby, mediates the biological outcome.

show abstract

“…Elevated or imbalanced dNTP pools can result in a mutator phenotype (25, 193, 194) that disrupt genomic integrity and DNA replication and repair (195–197). Conversely, dNTP pool depletion can result in genomic instability that progresses to cancer (198).…”

Section: Samhd1 Mutations Results In Diseasementioning

confidence: 99%

SAMHD1: Recurring roles in cell cycle, viral restriction, cancer, and innate immunity

Mauney

Hollis

2018

Autoimmunity

View full text Add to dashboard Cite

SAMHD1 is a deoxynucleotide triphosphate (dNTP) hydrolase that plays an important role in the homeostatic balance of cellular dNTPs. Its emerging role as an effector of innate immunity is affirmed by mutations in the SAMHD1 gene that cause the severe autoimmune disease, Aicardi-Goutieres syndrome (AGS) and that are linked to cancer. Additionally, SAMHD1 functions as a restriction factor for retroviruses such as HIV. Here we review the current biochemical and biological properties of the enzyme including its structure, activity, and regulation by post-translational modifications in the context of its cellular function. We outline open questions regarding the biology of SAMHD1 whose answers will be important for understanding its function as a regulator of cell cycle progression, genomic integrity, and in autoimmunity.

show abstract

Pools and Pols: Mechanism of a mutator phenotype

Cited by 9 publications

References 23 publications

Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance

Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance

Oxidative guanine base damage regulates human telomerase activity

SAMHD1: Recurring roles in cell cycle, viral restriction, cancer, and innate immunity

Contact Info

Product

Resources

About