Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Comment
. 2017 May 30;114(22):5561-5563.
doi: 10.1073/pnas.1705971114. Epub 2017 May 22.

DNA replication and mismatch repair safeguard against metabolic imbalances

Carol M Manhart  1 , Eric Alani  2
Affiliations
Comment

DNA replication and mismatch repair safeguard against metabolic imbalances

Carol M Manhart et al. Proc Natl Acad Sci U S A. .
No abstract available

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Removing the buffering capabilities of DNA replication and DNA MMR uncovers new factors that contribute to nucleotide pool homeostasis. Multiple mechanisms contribute to the overall fidelity of DNA replication. For example, each of the four mechanisms outlined in this figure can compensate for defects in the others. (i) A homeostasis mechanism responds to cellular metabolism to regulate the biosynthesis of dNTP and dNTP precursors to maintain a balanced concentration of dNTPs. (ii) DNA polymerase proofreading activities: During eukaryotic DNA replication, the major replicative polymerases Polε and Polδ both contain proofreading activities that enable them to excise misincorporation errors. However, Polα, which initiates DNA synthesis at origins and at Okazaki fragments, does not contain such a function. (iii) DNA MMR: MMR identifies mismatches resulting primarily from DNA replication errors. Nascent DNA is excised by the MMR machinery and is subsequently repaired by DNA synthesis. The MMR protein machinery can become saturated when there is an abundance of replication errors, allowing mismatches to escape repair. (iv) DNA polymerase selectivity: Polε and Polδ are high-fidelity replicative polymerases but can differ by ∼10-fold in their ability to incorporate the correct base (14). In contrast, translesion synthesis DNA polymerases are highly error-prone. When multiple mechanisms are defective, buffering fails and mutation rates increase significantly.
See this image and copyright information in PMC

Comment on

References

    1. Kunkel TA, Erie DA. Eukaryotic mismatch repair in relation to DNA replication. Annu Rev Genet. 2015;49:291–313. - PMC - PubMed
    1. Morrison A, Johnson AL, Johnston LH, Sugino A. Pathway correcting DNA replication errors in Saccharomyces cerevisiae. EMBO J. 1993;12:1467–1473. - PMC - PubMed
    1. Loeb LA, Monnat RJ., Jr DNA polymerases and human disease. Nat Rev Genet. 2008;9:594–604. - PubMed
    1. Schmidt TT, et al. Alterations in cellular metabolism triggered by URA7 or GLN3 inactivation cause imbalanced dNTP pools and increased mutagenesis. Proc Natl Acad Sci USA. 2017;114:E4442–E4451. - PMC - PubMed
    1. Huang M-E, Rio A-G, Nicolas A, Kolodner RD. A genomewide screen in Saccharomyces cerevisiae for genes that suppress the accumulation of mutations. Proc Natl Acad Sci USA. 2003;100:11529–11534. - PMC - PubMed

Publication types

LinkOut - more resources