The following statements refer to factors regulating the fidelity of DNA replication:

A. The 5’ to 3’ exonuclease activity of the replicative DNA polymerase.
B. Imbalanced intracellular concentrations of the four dNTPs.
C. Increased intracellular concentrations of rNTPs resulting in increased incorporation of rNTPs during DNA synthesis, which are not easily removed by the polymerase’s proofreading activity.
D. Removal of incorrectly incorporated nucleotides by the mismatch repair system.

Which one of the following options gives the combination of all correct statements?

Correct option is B

Fidelity in DNA replication is crucial for maintaining genetic stability. Several factors influence the accuracy of replication, including proofreading by DNA polymerase, nucleotide balance, and mismatch repair systems.

1. Statement A: Incorrect 

   • The statement mentions "5' to 3' exonuclease activity", which is not the proofreading function of DNA polymerase.
   • The correct proofreading activity occurs via "3' to 5' exonuclease" activity, which allows DNA polymerase to remove incorrectly incorporated nucleotides.
   • The 5' to 3' exonuclease activity is primarily involved in RNA primer removal, not proofreading.
   • Since the statement is incorrect due to the wrong exonuclease direction, A is incorrect.

2. Statement B: Correct 

   • The concentration of the four dNTPs (deoxyribonucleoside triphosphates) affects DNA replication fidelity.
   • An imbalance can lead to an increased mutation rate because some nucleotides may be misincorporated more frequently.
   • Proper dNTP homeostasis ensures that the correct nucleotide is available at the right time.

3. Statement C: Correct 

   • Increased intracellular concentrations of rNTPs (ribonucleotides) can cause misincorporation into DNA.
   • Although DNA polymerase prefers dNTPs over rNTPs, some rNTPs can still be mistakenly incorporated, leading to replication errors.
   • The proofreading activity of DNA polymerase is inefficient at removing rNTPs, making their misincorporation problematic.
   • RNase H plays a role in fixing these errors, but the initial prevention of rNTP incorporation is crucial.

4. Statement D: Correct 

   • The Mismatch Repair (MMR) system corrects errors left behind after DNA replication, increasing overall fidelity.
   • MutS, MutL, and MutH proteins detect and remove mismatched bases that escape the proofreading activity of DNA polymerase.
   • Mutations in MMR genes (e.g., MLH1, MSH2) can lead to genetic disorders such as Lynch syndrome (hereditary nonpolyposis colorectal cancer, HNPCC).

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