Replisome - Challenges of DNA Replication

Challenges of DNA Replication

The replisome is a system in which various factors work together to solve the structural and chemical challenges of DNA replication. Chromosomes size and structure varies between organisms, but since DNA molecules are the reservoir of genetic information for all forms of life, many replication challenges and solutions are the same for different organisms. As a result, the replication factors that solve these problems are highly conserved in terms of structure, chemistry, functionality, or sequence. General structural and chemical challenges include the following:

  • Efficient replisome assembly at origins of replication (origin recognition complexes or specific replication origin sequences in some organisms)
  • Separating the duplex into the leading and lagging template strands (helicases)
  • Protecting the leading and lagging strands from damage after duplex separation (SSB and RPA factors)
  • Priming of the leading and lagging template strands (primase or DNA polymerase alpha)
  • Ensuring processivity (clamp loading factors, ring-shaped clamp proteins, strand binding proteins)
  • High-fidelity DNA replication (DNA polymerase III, DNA polymerase delta, DNA polymerase epsilon. All have intrinsically low error rates because of their structure and chemistry.)
  • Error correction (replicative polymerase active sites sense errors; 3' to 5' exonuclease domains of replicative polymerases fix errors)
  • Synchronised polymerisation of leading and lagging strands despite anti-parallel structure (replication fork structure, dimerisation of replicative polymerases)
  • Primer removal (DNA polymerase I, RNAse H, flap endonucleases such as FEN1, or other DNA repair factors)
  • Formation of phosphodiester bonds at gaps between Okazaki fragments (ligase)

In general, the challenges of DNA replication involve the structure of the molecules, the chemistry of the molecules, and, from a systems perspective, the underlying relationships between the structure and the chemistry.

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