‘PIPs’ in DNA polymerase: PCNA interaction affairs

Abstract

Interaction of PCNA with DNA polymerase is vital to efficient and processive DNA synthesis. PCNA being a homotrimeric ring possesses three hydrophobic pockets mostly involved in an interaction with its binding partners. PCNA interacting proteins contain a short sequence of eight amino acids, popularly coined as PIP motif, which snuggly fits into the hydrophobic pocket of PCNA to stabilize the interaction. In the last two decades, several PIP motifs have been mapped or predicted in eukaryotic DNA polymerases. In this review, we summarize our understandings of DNA polymerase-PCNA interaction, the function of such interaction during DNA synthesis, and emphasize the lacunae that persist. Because of the presence of multiple ligands in the replisome complex and due to many interaction sites in DNA polymerases, we also propose two modes of DNA polymerase positioning on PCNA required for DNA synthesis to rationalize the tool-belt model of DNA replication.

Structural analyses of PCNA from the fungal pathogen Candida albicans identify three regions with species‐specific conformations

“…By physically interacting with replicative DNA polymerases such as DNA polymerase delta, PCNA stimulates their processivity several hundred‐fold [3–5]. Besides DNA replication, PCNA plays a pivotal role by acting as a docking station for an array of protein factors involved in DNA damage response, chromatin assembly, cell cycle control and chromatin remodelling [6,7]. The DNA sliding clamp or PCNA is evolutionarily conserved across species in various domains of life.…”

The ubiquitin-binding domain of DNA polymerase η directly binds to DNA clamp PCNA and regulates translesion DNA synthesis

“…Thus, even in S. cerevisiae Pol, the ubz domain can bind to PCNA provided the pip is completely absent in the C-terminal domain. Unlike the pip motif that forms a flexible 310 helix and gets stabilized into the hydrophobic pocket of the IDCL in PCNA trimer, ubz is structurally more organized, consisting of two antiparallel -strands and an  helix (4,32). Since the D626A CaPol J o u r n a l P r e -p r o o f 14 mutant did not bind to PCNA and failed to suppress the UV sensitivity of S. cerevisiae rad30 strain, the -helix of CaPol may be the site of PCNA interaction.…”

“…A pip motif consists of a consensus sequence of eight amino acids QxxhxxFF(or YF/FY/YY/FL), where x is any amino acid, and h is any hydrophobic residue. PCNA interaction motifs have been mapped in all the Y-family polymerases from S. cerevisiae and humans, except in Rev1 (4).…”

“…Timely recruitment of specific TLS pols to a specific lesion site and their regulated activity determine the stability of a cell’s genome. Deciphering underlying mechanisms by which TLS pols gain access to the template–primer junction and take over synthesis from the replicative pol is crucial to understand the dynamic behavior of the replication fork during translesion DNA synthesis ( 4 ).…”

SerpinB10, a Serine Protease Inhibitor, Is Implicated in UV-Induced Cellular Response

“…To rescue the stalled replication machinery, eukaryotic cells have evolved error-prone translesion (TLS) DNA polymerases, which can pass through the lesions. However, to keep these low-fidelity TLS polymerases away from the undamaged DNA, interaction is required between them and the proliferating cell nuclear antigen (PCNA), which serves as a binding platform for proteins involved in the recognition and repair of damage [7][8][9][10][11][12][13]. One of the main steps in the exchange of replicative polymerases to TLS DNA polymerases at stalled replication forks is monoubiquitylation; hence, the activation of PCNA, mediated by Rad6 and Rad18 ubiquitin ligases, is a crucial step for successful repair [7,10,[14][15][16][17].…”