Effects of PCNA Stability on the Formation of Mutations

The fidelity of replication, especially in the presence of DNA damage, is essential for the proper function of cells. Mutations that inactivate genes involved in DNA damage repair or bypass are enriched in several types of cancer cells. Thus, it is important to further our understanding of the mecha...

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Bibliographic Details
Published in:International journal of molecular sciences 2024-08, Vol.25 (16), p.8646
Main Authors: Arbel-Groissman, Matan, Liefshitz, Batia, Kupiec, Martin
Format: Article
Language:English
Subjects:
Cancer
Chromatin - genetics
Chromatin - metabolism
DNA - genetics
DNA - metabolism
DNA Damage
DNA polymerase
DNA Replication
Genes
Genomes
Humans
Mutation
Proliferating Cell Nuclear Antigen - genetics
Proliferating Cell Nuclear Antigen - metabolism
Protein Stability
Proteins
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Summary:The fidelity of replication, especially in the presence of DNA damage, is essential for the proper function of cells. Mutations that inactivate genes involved in DNA damage repair or bypass are enriched in several types of cancer cells. Thus, it is important to further our understanding of the mechanisms governing replication fidelity. PCNA is a ring-shaped complex that encircles DNA at the front of the replication fork, at the double-stranded/single-stranded DNA junction. It serves as a processivity factor for the different DNA replication polymerases, allowing them to replicate longer stretches of DNA by physically tethering them to the DNA and preventing their detachment. In addition, PCNA also regulates and coordinates different DNA damage bypass pathways meant to allow DNA replication in the presence of DNA damage. Due to its essentiality and the numerous functions it has in the cell, much is still unclear about PCNA. Here, we utilize PCNA mutants that lower the stability of the PCNA complex on the chromatin, and thus tend to disassociate and fall from the DNA. Using these mutants, we show that PCNA's physical presence on the DNA can prevent DNA misalignment at repetitive sequences, leading to increased mutation formation. We also show that PCNA-interacting proteins play an important role in strengthening the ring's stability on the chromatin. Such repetitive sequence-induced mutations are common in several human diseases and it is important to study their formation and the mechanisms guarding against them.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms25168646