JMJD1B-mediated FEN1 demethylation allows timely switching of Okazaki fragment maturation core enzymes to avoid mutagenic flap ligation by PARP1-LIG3
These videos have been matched automatically. Contact us if they are not relevant.
These videos have been matched automatically. Contact us if they are not relevant.
View abstract on PubMed
Summary
This summary is machine-generated.Okazaki fragment maturation relies on sequential enzyme binding to PCNA. Methylation regulates this process, and its disruption leads to DNA mutations, impacting cell survival.
Area Of Science
- Molecular Biology
- Genetics
- Biochemistry
Background
- Okazaki fragment maturation (OFM) is essential for DNA replication fidelity.
- This process involves coordinated actions of DNA Polymerase delta (Polδ), Flap Endonuclease 1 (FEN1), and DNA Ligase 1 (LIG1) interacting with Proliferating Cell Nuclear Antigen (PCNA).
Purpose Of The Study
- To elucidate the sequential binding mechanism of Polδ, FEN1, and LIG1 to PCNA during OFM.
- To investigate the role of FEN1 methylation and demethylation in regulating this PCNA-binding program and its impact on DNA replication and mutagenesis.
Main Methods
- Demonstration of sequential PCNA binding by Polδ, FEN1, and LIG1 in mammalian cells.
- Analysis of FEN1 R192 methylation and its regulation by the arginine demethylase JMJD1B.
- Investigation of cellular consequences in R192Q mutant and <i>Jmjd1b</i> knockout cells.
Main Results
- FEN1, Polδ, and LIG1 bind sequentially, not simultaneously, to PCNA.
- FEN1 R192 methylation mediates PCNA association and prevents premature LIG1 loading.
- FEN1 demethylation by JMJD1B facilitates FEN1 dissociation from PCNA and promotes LIG1 recruitment.
- Disruption of sequential binding leads to unprocessed flaps, alternative OFM via LIG3, and increased DNA mutations.
Conclusions
- The study defines a fundamental, sequential PCNA-binding program critical for OFM.
- Alternative OFM pathways involving LIG3 can support cell survival but at the cost of genomic instability.
- Findings reveal mechanisms underlying DNA replication fidelity and mutagenesis.
These videos have been matched automatically. Contact us if they are not relevant.
These videos have been matched automatically. Contact us if they are not relevant.
Related Concept Videos
DNA replication is initiated at sites containing predefined DNA sequences known as origins of replication. DNA is unwound at these sites by the minichromosome maintenance (MCM) helicase and other factors such as Cdc45 and the associated GINS complex.The unwound single strands are protected by replication protein A (RPA) until DNA polymerase starts synthesizing DNA at the 5’ end of the strand in the same direction as the replication fork. To prevent the replication fork from falling apart,...
Since the discovery of the two BER pathways, there has been a debate about how a cell chooses one pathway over the other and the factors determining this selection. Numerous in vitro experiments have pointed out multiple determinants for the sub-pathway selection. These are:
Lesion type: Depending on the type of base damage, a specific DNA glycosylase - mono or bifunctional, is recruited to the damaged site. While the sequential action of a monofunctional glycosylase favors long patch 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...
Overview
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...
In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...