Question

Explain what would happen during DNA replication if both DNA Pol I and DNA Pol III had high processivity. in writing no diagrams or pictures

Answer 1

The genomes, from the smallest to the largest, provide an enormous challenge for the replicative DNA polymerases to faithfully copy to give the many generations that follow a comparable condition for life. In this article, we discuss the structural and functional bases by which replicative DNA polymerases are able to efficiently and faithfully build new copies of genomes in eubacteria, archaea, and eukaryotes.

Pol III holoenzyme is the E. coli chromosomal replicase that synthesizes both leading and lagging strands simultaneously. As isolated directly from cells, it has an average composition close to (αεθ)₂–(τ₂γδδ′ψχ)–(β₂)₂ (17 subunits), where αεθ is the polymerase core discussed in more detail below, β₂ is the sliding clamp, and τ₂γδδ′ψχ is the clamp loader complex that may contain two to three τ and one to zero γ subunits.

The αεθ core of Pol III is a tightly associated complex. The large α subunit is a family C polymerase, and ε is a separate 3′–5′ editing exonuclease subunit from the DnaQ family. The small θ subunit has a role in stabilizing ε, but it only occurs in a limited range of bacterial species. The α subunit is made up of a series of domains.The amino-terminal PHP domain seems to be a vestigial exonuclease domain that may still be functional as a proofreader in some species . In E. coli, it has evolved to be the site of interaction of the ε subunit. This domain is followed by the usual polymerase palm, thumb, and fingers domains, and a β-binding domain that contains a conserved clamp-binding motif that interacts with the β₂ clamp to tether α to the product DNA to ensure its high processivity. This is followed by an OB-fold domain that is likely to interact with the single-stranded template DNA, and a carboxy-terminal domain that interacts tightly with the carboxy-terminal domain of the τ subunit of the clamp loader. Because the clamp loader contains two (or three) τ subunits, at least two αεθ cores are maintained in the replicase complex, one each for leading- and lagging-strand synthesis.There is no crystal structure available of a complete Pol III core from any bacterium, but available structures of α subunits include E. coli α, which misses its internal clamp-binding motif and domains that follow it), and full-length Thermus aquaticus (Taq) α (DnaE), both by itself and in complex with primer-template DNA.

The other polymerase that plays a significant role in bacterial DNA replication is Pol I, the founding member of the family A polymerases . Its primary function in replication is in Okazaki fragment processing on the lagging strand. Pol III is capable of synthesizing Okazaki fragments right up to the 5′ end of a preceding RNA primer, whereupon it is recycled to a new primer terminus, leaving behind a nick or short gap . Pol I has three separate activities in a single polypeptide chain. The amino-terminal domain is a 5′–3′ exonuclease capable of excising the RNA primers at the same time as the carboxy-terminal polymerase domain (with thumb, palm, and fingers subdomains) extends the DNA primer behind it. The central domain is a DnaQ family proofreading exonuclease used to ensure high fidelity. Thus, Pol I uses a process of “nick translation” to replace RNA primers with DNA, leaving a nick with a 3′-OH and 5′-phosphate that is a substrate for DNA ligase, which seals the nick to make a contiguous lagging strand.

DNA replication is an essential process in all organisms. Although there are sufficient variations in structures among replisomal proteins from bacteria and humans to make replisomes a very good target for discovery of new antibacterial therapeutics, it is a target that is surprisingly underexploited both by pharmaceutical companies and in nature by other organisms. Although there are no known inhibitors of DnaE-type Pol IIIs, there have been substantial efforts to target Pol C from Gram-positive bacteria, including Staphylococcus aureus, using a range of 6-anilinouracils (6-AUs) and quinazolin-2-ylamino-quinazolin-4-ols.

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