The Role of MutY and Alternative Pathways in Repairing 8-oxo-G:A Mispairs in E. coli

Oxidative damage to DNA is a common source of mutations in all living organisms. In Escherichia coli, guanine (G) bases can be oxidized to form 8-oxo-7,8-dihydroguanine (8-oxo-G), which is highly mutagenic. If left unrepaired, 8-oxo-G can pair with adenine (A) during DNA replication, leading to G:C → T:A transversion mutations. To counteract this, E. coli has evolved a sophisticated repair system involving specific DNA glycosylases. This article explores how E. coli handles 8-oxo-G lesions, the role of MutY, and what happens when MutY is absent—addressing the implications for mutation prevention and cell survival.

Oxidative Damage and 8-oxo-G Formation

Oxidative stress—caused by reactive oxygen species (ROS)—can modify guanine in DNA, producing 8-oxo-G. This lesion is problematic because it can mispair with adenine during DNA replication, resulting in a 8-oxo-G:A mismatch instead of the normal G:C pair.

The Threat of 8-oxo-G:A Mispairs

If the 8-oxo-G:A mispair is not corrected, the next round of DNA replication will result in a G:C → T:A transversion mutation. This is because:

• First replication: 8-oxo-G (from the original strand) pairs with A (incorporated by DNA polymerase).

• Second replication: The A in the new strand pairs with T, resulting in a T:A pair where there was originally a G:C pair.

The Role of DNA Glycosylases in Repairing 8-oxo-G Lesions

E. coli uses two main DNA glycosylases to prevent mutations from 8-oxo-G:

• MutM (Fpg): Recognizes and removes 8-oxo-G from DNA before replication, preventing its mispairing with A.

• MutY: Recognizes and removes A that has been misincorporated opposite 8-oxo-G after replication, correcting the mispair before a mutation is fixed.

What Happens When MutY Is Deleted?

When the MutY gene is deleted in E. coli, the strain still survives. This observation is significant and suggests that:

• MutY is not absolutely essential for survival under normal laboratory conditions.

• Alternative repair pathways may exist to correct or tolerate 8-oxo-G:A mispairs.

However, MutY-deficient strains do have a higher mutation rate, indicating that MutY plays a critical role in mutation prevention, but its absence does not result in inviability.

Why the Other Options Are Incorrect

Let’s analyze each option:

• (1) MutY is not responsible for the excision of ‘A’ incorporated against 8-oxo-G:

  • Incorrect. MutY is specifically responsible for excising A paired with 8-oxo-G.

• (2) Alternate DNA repair pathways may substitute for the repair of ‘A’ incorporated against 8-oxo-G:

  • Correct. The survival of E. coli in the absence of MutY suggests that other pathways can partially compensate for its loss, though not as efficiently.

• (3) Incorporation of ‘A’ against 8-oxo-G does not cause mutation in E. coli:

  • Incorrect. Incorporation of A against 8-oxo-G does cause mutations, which is why MutY is important.

• (4) The 8-oxo-G:A base pair in DNA distorts its structure in such a way that, during the next round of replication a ‘G’ is incorporated against ‘A’ in the 8-oxo-G:A mispair:

  • Incorrect. The distortion does not ensure that G is incorporated against A; instead, T is incorporated, leading to mutations.

The Correct Answer

Option (2): Alternate DNA repair pathways may substitute for the repair of ‘A’ incorporated against 8-oxo-G

This is supported by the observation that E. coli survives without MutY, indicating that other mechanisms can partially compensate for its absence, though the mutation rate increases.

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• 8-oxo-G DNA damage

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• 8-oxo-G:A mispair

• G:C to T:A transversion

• E. coli DNA repair

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Conclusion

The survival of E. coli in the absence of MutY demonstrates that alternative DNA repair pathways can partially substitute for the repair of A incorporated against 8-oxo-G, though not as efficiently. This highlights the robustness and redundancy of DNA repair systems in maintaining genomic integrity. The correct answer is option (2): Alternate DNA repair pathways may substitute for the repair of ‘A’ incorporated against 8-oxo-G.