DNA Repair (ad)cloudfront.net/thumbnails/7c07a885-3c5d-5344-829d-b0ceb1cf7024/fab81a65-2c50-5a4f-a0f6-a4279f631876.jpg”>
Mismatch repair ensures that the errors in leading strand replication are corrected. This review will describe how MMR operates on the leading strand, focusing mainly on mechanisms of action and its efficiency as well as interactions with different DNA polymerases.
Mechanisms of Mismatch Repair
MMR exerts a fully conserved function in re-preventing base-pair mispairing or corrects them during DNA replication. It mainly aims for escape errors through the proofreading activity of DNA polymerases. Specific proteins such as MutS and MutL are able to recognize mispaired bases, which leads them to activate the MMR system detecting mismatches. If a mismatch is detected the repair machinery will remove and resynthesize that fragment using as template to copy it correctly, its opposite strand23.
For even the most basic overview of what we are talking about here, you might want to look up leading strand vs. lagging strand.
Leading Strand is synthesized continuously, the lagging strand is synthesised in short fragments — Okazaki Fragments.
These strands are synthesized differently and hence MMR acts different on them. Depending on the type of error strand-specific, leading-strand errors could be rarer but more harmful if not removed4.
Efficiency of Mismatch Repair
Studies show that MMR is biased for the fidelity of both leading and lagging strands, but this bias varies with conditions:
Polymerase: Various DNA polymerases have different fidelities (Pol ε is the main polymerase for leading strand synthesis and it has high fidelity?
Type of Mismatch Composition: Some mismatches are harder for MMR to fix. T-T mismatches are resistant to repair 2, as is an example.
Position of Mismatches: The efficiency of MMR is also a function of the location on the DNA strand in which mismatches are generated. It is possible that certain areas of the genome are constitutively resistant to MMR activity resulting in these localized higher mutation rates24.
FORENSIC IMPLICATIONS OF GENOME STABILITY
A competent action by MMR in repairing leading strand errors is crucial for the maintenance of genomic stability. Failure of this repair mechanism allows an increase in mutation rate and has been linked to different types of cancer. Studies aimed to define the influence of MMR on several DNA polymerases offer new targets for cancer therapy15.
Overall, it is clear that mismatch repair plays a paramount role in keeping the leading strand accurate during DNA replication by fixing mistakes which could entail mutations. Efficiency was shown to depend on polymerase type, mismatch composition and location, showing its complexity and relevance in genomic stability.
