Protein-Protein Interactions in Translesion Synthesis.

Radha Charan Dash,Kyle Hadden

doi:10.3390/molecules26185544

Radha Charan Dash, Kyle Hadden

Open Access

https://doi.org/10.3390/molecules26185544

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Journal: Molecules (Basel, Switzerland)	Publication Date: Sep 13, 2021
Citations: 6	License type: CC BY 4.0

Affiliation: University of Connecticut

Abstract

Translesion synthesis (TLS) is an error-prone DNA damage tolerance mechanism used by actively replicating cells to copy past DNA lesions and extend the primer strand. TLS ensures that cells continue replication in the presence of damaged DNA bases, albeit at the expense of an increased mutation rate. Recent studies have demonstrated a clear role for TLS in rescuing cancer cells treated with first-line genotoxic agents by allowing them to replicate and survive in the presence of chemotherapy-induced DNA lesions. The importance of TLS in both the initial response to chemotherapy and the long-term development of acquired resistance has allowed it to emerge as an interesting target for small molecule drug discovery. Proper TLS function is a complicated process involving a heteroprotein complex that mediates multiple attachment and switching steps through several protein–protein interactions (PPIs). In this review, we briefly describe the importance of TLS in cancer and provide an in-depth analysis of key TLS PPIs, focusing on key structural features at the PPI interface while also exploring the potential druggability of each key PPI.

Highlights

DNA damage is an abnormal change in the basic structure of DNA that can be caused by external agents such as sunlight, ionizing radiation, chemotherapy as well as intracellular metabolism [1]
translesion synthesis (TLS) and template switching (TS) are utilized for single-strand DNA legion lesion repair and homology-dependent repair of double-strand breaks (DSBs)
Key interactions at the various TLS protein–protein interactions (PPIs) interfaces are described throughout the text with detailed descriptions of all the intermolecular interactions, and the energy terms that govern these TLS PPIs are provided in the Supplementary Tables

Summary

Introduction

DNA damage is an abnormal change in the basic structure of DNA that can be caused by external agents such as sunlight, ionizing radiation, chemotherapy as well as intracellular metabolism [1]. Deubiquitination and/or ISGylation of PCNA results in release of the error-prone TLS POLs after bypass completion, allowing normal replication to restart [25] TLS in cancer cells can bypass these lesions, preventing apoptosis and resulting in a surviving population of tumor cells with increased mutations and a greater potential to develop acquired resistance to the first-line agent(s). Disruption of REV1/POLζ-dependent TLS in a variety of cancer models restores sensitivity to several genotoxic agents, reduces tumor progression, and can increase overall survival. SScchheemmaattiicc iilllluussttrraattiioonn ooff tthhee ddoommaaiinn ssttrruuccttuurreess ooff YY--ffaammiillyy PPOOLLss ((AA)) aanndd tthhee mmuullttii-ssuubbuunniittTTLLSS eennzzyymmee PPOOLLζζ ((BB)).. PPOOLLDD22 bbiinnddss RREEVV33LL aatt tthhee CCTTDD,, ccoooorrddiinnaatteedd bbyy tthhee iirroonn--ssuullffuurr((44FFee--44SS))cclulussteter.r. RREEVV11 bbiinnddss hhuummaannPPOOLLζζ tthhrroouugghh iinntteerraaccttiioonnss wwiitthh RREEVV77 aanndd PPOOLLDD33. Key interactions at the various TLS PPI interfaces are described throughout the text with detailed descriptions of all the intermolecular interactions, and the energy terms that govern these TLS PPIs are provided in the Supplementary Tables

PCNA PPIs

REV1 PPIs

POLζ PPIs