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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

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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.
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