U01.01.006 DNA replication

Eukaryotic DNA replication is more complex than in prokaryotes but uses many analogous enzymes. In both prokaryotes and eukaryotes, DNA replication is semiconservative, involves continuous and discontinuous (Okazaki fragment) synthesis, and occurs in the 5′ to 3′ direction.

Key Components and Functions

Component	Function	Clinical Notes/Mnemonics
Origin of Replication	Particular consensus sequence in the genome where DNA replication begins. Single origin in prokaryotes; multiple origins in eukaryotes.	AT-rich sequences (e.g., TATA box regions) are found in promoters and origins of replication.
Replication Fork	Y-shaped region along the DNA template where leading and lagging strands are synthesized.
Helicase	Unwinds DNA template at the replication fork.	Helicase Halves DNA. Deficiency in Bloom syndrome (BLM gene mutation).
Single-Stranded Binding Proteins	Prevent strands from reannealing.
DNA Topoisomerases	Create single- or double-stranded breaks in the helix to add or remove supercoils.	Eukaryotes: irinotecan/topotecan inhibit TOP I, etoposide/teniposide inhibit TOP II. Prokaryotes: fluoroquinolones inhibit TOP II (DNA gyrase) and TOP IV.
Primase	Synthesizes an RNA primer on which DNA polymerase III can initiate replication.
DNA Polymerase III (Prokaryotes)	Elongates leading strand by adding deoxynucleotides to the 3′ end. Elongates lagging strand until it reaches the primer of the preceding fragment.	Has 5′ to 3′ synthesis and 3′ to 5′ exonuclease activity. Drugs blocking DNA replication often have a modified 3′ OH, preventing addition of the next nucleotide (“chain termination”).
DNA Polymerase I (Prokaryotes)	Degrades RNA primer; replaces it with DNA. Excises RNA primer with 5′ to 3′ exonuclease activity.
DNA Ligase	Catalyzes the formation of a phosphodiester bond within a strand of double-stranded DNA, joining Okazaki fragments.	Ligase Links DNA.
Telomerase (Eukaryotes)	Adds DNA (TTAGGG) to 3′ ends of chromosomes to prevent loss of genetic material with each duplication.	Often dysregulated in cancer cells, allowing unlimited replication. Telomerase TAGs for Greatness and Glory.

Points to Remember

Replication Direction: DNA replication is semiconservative and occurs in the 5′ to 3′ direction.
Origin of Replication: AT-rich sequences are common.
Enzyme Functions:
- Helicase unwinds DNA.
- Single-stranded binding proteins prevent reannealing.
- Topoisomerases manage supercoiling.
- Primase synthesizes RNA primers.
- DNA polymerase III and I are crucial in prokaryotes for elongation and primer removal, respectively.
- DNA ligase joins Okazaki fragments.
- Telomerase prevents the loss of genetic material in eukaryotes and is linked to cancer cell immortality.

USMLE Step 1 Review Series

Curriculum

U01.01.006 DNA replication

Key Components and Functions

Points to Remember

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