Replication Fork

BioCodeKb - Bioinformatics Knowledgebase

The replication fork is a structure that forms within the long helical DNA during DNA replication. It is created by helicases, which break the hydrogen bonds holding the two DNA strands together in the helix. The replication origin forms a Y shape, called a replication fork. The resulting structure has two branching "prongs", each one made up of a single strand of DNA.


DNA replication occurs during the synthesis (S) phase of the cell cycle and starts at predefined DNA sequences known as replication origins, this start is also known as origin firing. Once the origins of replication have fired, the DNA replication proteins organize into a structure called the replication fork (RF), where a group of proteins coordinate DNA replication. It is called a fork because the simplified structure resembles a two-tined fork, but its function is hardly simple, since it is the location of dynamic activity among a large group of proteins. A copy of the DNA is made just prior to when a cell is going to split to create two cells. In order for this replication of DNA to take place, the DNA has to be in an orientation that will allow the replication machinery to make a copy. Our DNA is double-stranded, with the strands being held together by hydrogen bonds. The normal structure of our DNA when it is not being copied is a double helix. This looks very similar to a winding staircase. In this normal form, the DNA cannot be copied. DNA helicase is needed in order to open the DNA to expose the nucleotide bases that are used as the template for replicating the DNA. The area of the DNA that is opened by DNA helicase is known as the replication fork because it looks very similar to a fork in the road.


Partial separation of the double helix forms a replication fork. The replication fork is the area where the replication of DNA will actually take place. There are two strands of DNA that are exposed once the double helix is opened. One strand is known as the leading strand, and the other strand is known as the lagging strand. Two replication forks at the origin of replication are extended bi-directionally as replication proceeds. Single-strand binding proteins coat the strands of DNA near the replication fork to prevent the single-stranded DNA from winding back into a double helix.


Two main activities happen at the fork, DNA unwinding and DNA synthesis. The RF unwinds the unreplicated DNA ahead of it through a helicase enzyme complex. As their name suggests, helicases modify the structure of the DNA helix and promote unwinding and separation of the two DNA strands. The second activity of DNA synthesis at the RF is undertaken by DNA polymerase. This enzyme links together, or polymerizes, DNA bases in the correct sequence using the template DNA strand, and it generates two copies of the genome that are later divided into daughter cells in metaphase, or M phase.


Importance

  • Fork stability maintains genome stability

  • Fork stability has little effect on DNA replication if removed then affects sister chromatid cohesion

  • Connects helicase and polymerase epsilon plays role in RF stability

  • Involved in checkpoint signaling

  • Interacts directly with CHK1/RAD53/CDS1 effector kinases, as well as MUS81 nuclease

  • Connects helicase and polymerase alpha

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