Introduction

Fidelity of DNA replication is essential for maintaining genetic stability and preventing mutations. Multiple mechanisms work together to ensure that DNA polymerases accurately copy the genome with minimal errors. These mechanisms include nucleotide selectivity, proofreading by DNA polymerases, balanced intracellular dNTP pools, and post-replicative mismatch repair.

Analysis of the Statements on Fidelity Regulation

A. The 5′→3′ exonuclease activity of the replicative DNA polymerase

• This activity primarily removes RNA primers during lagging strand synthesis.

• It is not directly involved in enhancing replication fidelity or correcting errors during DNA synthesis.

• Therefore, statement A is not correct as a factor regulating fidelity.

B. Imbalanced intracellular concentrations of the four dNTPs

• Imbalanced dNTP pools increase the likelihood of misincorporation due to altered nucleotide availability.

• This imbalance reduces replication fidelity by increasing errors.

• Thus, statement B is correct.

C. Increased intracellular concentrations of INTPs resulting in increased incorporation of rNTPs during DNA synthesis, which are not easily removed by the polymerase’s proofreading activity

• Elevated rNTP (ribonucleotide) levels can lead to their incorporation into DNA.

• DNA polymerases have limited ability to remove ribonucleotides, leading to increased errors and genome instability.

• Statement C is correct.

D. Removal of incorrectly incorporated nucleotides by the mismatch repair system

• The mismatch repair (MMR) system scans newly synthesized DNA to identify and correct mismatches missed by polymerase proofreading.

• MMR significantly enhances replication fidelity post-synthesis.

• Statement D is correct.

Summary of Correct Statements

• B, C, and D are correct factors regulating replication fidelity.

• A is not directly involved in error correction or fidelity enhancement.

Final Answer

(2) B, C and D

Supporting Insights

• Proofreading and Mismatch Repair: DNA polymerases proofread via 3′→5′ exonuclease activity, but some errors escape this mechanism and are corrected by MMR.

• Nucleotide Pool Balance: Balanced dNTP pools are crucial; imbalances can increase mutation rates.

• Ribonucleotide Incorporation: High rNTP levels challenge DNA polymerase fidelity due to inefficient removal.

• 5′→3′ Exonuclease Role: Mainly involved in primer removal, not fidelity per se.

Summary Table

Keywords

DNA replication fidelity, proofreading, 3′→5′ exonuclease, 5′→3′ exonuclease, dNTP pool balance, ribonucleotide incorporation, mismatch repair system, DNA polymerase accuracy, genome stability, replication errors

Summary:
The fidelity of DNA replication is regulated by multiple factors. Imbalanced dNTP pools and increased ribonucleotide incorporation reduce fidelity by increasing errors during synthesis. The mismatch repair system corrects errors missed by polymerase proofreading, significantly enhancing accuracy. The 5′→3′ exonuclease activity, while essential for primer removal, does not directly regulate replication fidelity.

Correct answer:
(2) B, C and D