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Proofreading

Proofreading

Synthesis of new DNA molecules is carried out by the enzyme DNA polymerase, which adds nucleotides on the daughter strand complementary to the template DNA strand. DNA polymerase has a higher affinity to add the correct base and ensures fidelity during DNA replication. Furthermore, it exhibits proofreading activity during replication, using an exonuclease domain that cuts off incorrect nucleotides from the nascent DNA strand.
Errors During Replication are Corrected by the DNA Polymerase...

Proofreading

Proofreading

Nonsense-mediated mRNA Decay

Nonsense-mediated mRNA Decay

The Upf proteins that carry out nonsense-mediated decay (NMD) are found in all eukaryotic organisms, including humans. Each protein has an individual role, but they need to work in collaboration. Upf1 is an ATP-dependent RNA helicase that unwinds the RNA helix. Because Upf1 can unwind any RNA, Upf2 and Upf3 are required to help Upf1 discriminate between nonsense and normal mRNAs.
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...

Mismatch Repair

Mismatch Repair

Organisms are capable of detecting and fixing nucleotide mismatches that occur during DNA replication. This sophisticated process requires identifying the new strand and replacing the erroneous bases with correct nucleotides. Mismatch repair is coordinated by many proteins in both prokaryotes and eukaryotes.
The Mutator Protein Family Plays a Key Role in DNA Mismatch Repair
The human genome has more than 3 billion base pairs of DNA per cell. Prior to cell division, that vast amount of genetic...

Mismatch Repair

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Translesion DNA Polymerases

Translesion DNA Polymerases

Translesion (TLS) polymerases rescue stalled DNA polymerases at sites of damaged bases by replacing the replicative polymerase and installing a nucleotide across the damaged site. Doing so, TLS allows additional time for the cell to repair the damage before resuming regular DNA replication.
TLS polymerases are found in all three domains of life - archaea, bacteria, and eukaryotes. Of the different classes of TLS polymerases, members of the Y family are fitted with specialized structures that...

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Author Spotlight: Developing Novel Anticancer Therapeutics Targeting the DNA Damage Response

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Polμ tumor variants decrease the efficiency and accuracy of NHEJ.

Guillermo Sastre-Moreno¹, John M Pryor², Alberto Díaz-Talavera¹

¹Centro de Biología Molecular 'Severo Ochoa', Universidad Autónoma de Madrid/CSIC, Madrid, Spain.

Nucleic Acids Research

|October 4, 2017

Summary

This summary is machine-generated.

Two human Polμ mutations found in tumors reduce the accuracy of DNA double-strand break repair via non-homologous end-joining (NHEJ), increasing mutation risk. This highlights Polμ's role in maintaining genome stability.

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Rare Event Detection Using Error-corrected DNA and RNA Sequencing

Rare Event Detection Using Error-corrected DNA and RNA Sequencing

Published on: August 3, 2018

Area of Science:

Genetics
Molecular Biology
Cancer Research

Background:

DNA double-strand breaks (DSBs) are repaired by non-homologous end-joining (NHEJ).
Human cells utilize specialized DNA polymerases, Polλ and Polμ, for gap-filling during NHEJ.
Polμ is adapted for repairing DSBs with non-complementary ends, but the mechanisms are unclear.

Purpose of the Study:

Investigate the impact of specific Polμ mutations (G174S and R175H) on NHEJ efficiency and fidelity.
Elucidate the structural and functional consequences of these mutations in vitro and in vivo.
Determine the role of the Polμ 8 kDa domain in NHEJ accuracy.

Main Methods:

In vitro biochemical assays to assess Polμ activity and template dependency.
In vivo studies to evaluate NHEJ efficiency and fidelity in the presence of Polμ mutations.
Analysis of tumor-derived Polμ point mutations (G174S, R175H).

Main Results:

The G174S and R175H Polμ mutations significantly reduce NHEJ efficiency and accuracy.
Mutations decrease template dependency, leading to increased random nucleotide incorporation.
The 8 kDa domain of Polμ is crucial for both accurate and efficient NHEJ.

Conclusions:

Tumor-associated Polμ mutations can impair NHEJ, potentially contributing to genomic instability.
Altered template dependency in Polμ mutants increases error rates at DSBs.
This study provides the first evidence linking specific Polμ mutations to altered NHEJ fidelity in cancer.