From Processivity to Genome Maintenance: The Many Roles of Sliding Clamps

Abstract

Sliding clamps play a pivotal role in the process of replication by increasing the processivity of the replicative polymerase. They also serve as an interacting platform for a plethora of other proteins, which have an important role in other DNA metabolic processes, including DNA repair. In other words, clamps have evolved, as has been correctly referred to, into a mobile "tool-belt" on the DNA, and provide a platform for several proteins that are involved in maintaining genome integrity. Because of the central role played by the sliding clamp in various processes, its study becomes essential and relevant in understanding these processes and exploring the protein as an important drug target. In this review, we provide an updated report on the functioning, interactions, and moonlighting roles of the sliding clamps in various organisms and its utilization as a drug target.

Keywords: dimer; moonlight role; processivity factor; sliding clamp; trimer.

Figure 1

Comparison of a dimeric and a trimeric sliding clamp. The panel shows a comparison of a dimeric and a trimeric clamp. The dimeric clamp has three domains viz. domain I, domain II, and domain III, whereas a trimeric clamp has two domains viz. NTD (N-terminal domain) and CTD (C-terminal domain) per subunit. The broken line marks the subunit-subunit interface. Within a subunit, the two domains are connected through an amino acid region called the inter-domain connecting loop (IDCL). The image was generated using the Escherichia coli β-clamp (PDB ID: 1MMI) and human PCNA (PDB ID: 1VYM).

Figure 2

Sliding clamps from different organisms. Sliding clamp from T4 bacteriophage gp45 (1CZD), E. coli β clamp (1MMI), Pyrococcus furiosus PCNA (1GE8), Saccharomyces cerevisiae PCNA (1PLQ), and Homo sapiens PCNA (1VYM) are superimposed using PyMol. In the dimeric bacterial clamp (1MMI), three domains are colored in blue (I), green (II), and yellow (III), while in trimeric clamps, NTD is colored green and CTD, yellow; the IDLC is colored orange. The ‘N’ and ‘C’ faces of the clamps are shown. The enlarged subunit–subunit interface and hydrogen bonds are shown at the bottom of the figure.

Figure 3

The role of the sliding clamp during replication. (A) The figure represents the E. coli replisome and the position of the clamp. The sliding clamp is loaded onto the primer-template junction by the clamp loader complex. The clamp consists of two hydrophobic pockets through which the polymerase and other proteins of the replisome interact with it. (B) The clamp loader complex opens the clamp, loads it onto the DNA, and is then ejected with the hydrolysis of ATP. Once the synthesis of the Okazaki fragment is completed, the clamp, along with polymerase III, is released. Reprinted/adapted from ref [42] under the terms of Creative Commons license (full terms at http://creativecommons.org/licenses/by/4.0/ (accessed on 3 November 2022)).

Figure 4

gp45 mediated transcription activation. After the gp45 is loaded onto the DNA, gp55 and gp33 mediate the binding of gp45 with the RNAP. The three proteins, along with the RNAP, start the promoter scanning process along the DNA, and initiate transcription upon interaction with a promoter. Gray, RNAP; light orange, gp44; dark orange, gp62; cyan, gp45; yellow, gp55; dark green, gp33; salmon, nontemplate-strand DNA; red, template-strand DNA; blue, -10-like element; magenta, RNA. Reprinted from ref [65] under the terms of the Creative Commons CC BY license (full terms at http://creativecommons.org/licenses/by/4.0/ (accessed on 3 November 2022)).

Figure 5

Overview of PCNA in DNA repair mechanisms. Reprinted from ref [66] under the terms and conditions of the Creative Commons Attribution (CC BY) license (full terms at http://creativecommons.org/licenses/by/4.0/ (accessed on 3 November 2022)).

Figure 6

The many roles of a sliding clamp. The image shows the many physiological processes in which the sliding clamp is involved in bacteriophages, prokaryotes, and eukaryotes. The image was created with www.biorender.com (accessed on 28 September 2022).