Zuo1 supports G4 structure formation and directs repair toward nucleotide excision repair

Alessio De Magis,Katrin Paeschke,Marco Caterino,Mona Hajikazemi,Silvia Götz,Stefan Juranek,Enikő Fekete-Szücs

doi:10.1038/s41467-020-17701-8

Alessio De Magis, Katrin Paeschke + Show 5 more

Open Access

https://doi.org/10.1038/s41467-020-17701-8

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Abstract

Nucleic acids can fold into G-quadruplex (G4) structures that can fine-tune biological processes. Proteins are required to recognize G4 structures and coordinate their function. Here we identify Zuo1 as a novel G4-binding protein in vitro and in vivo. In vivo in the absence of Zuo1 fewer G4 structures form, cell growth slows and cells become UV sensitive. Subsequent experiments reveal that these cellular changes are due to reduced levels of G4 structures. Zuo1 function at G4 structures results in the recruitment of nucleotide excision repair (NER) factors, which has a positive effect on genome stability. Cells lacking functional NER, as well as Zuo1, accumulate G4 structures, which become accessible to translesion synthesis. Our results suggest a model in which Zuo1 supports NER function and regulates the choice of the DNA repair pathway nearby G4 structures.

Highlights

Nucleic acids can fold into G-quadruplex (G4) structures that can fine-tune biological processes
The in vitro folding of G4 motif from chromosome IX (G4IX) into a parallel quadruplex was confirmed by circular dichroism (CD), with characteristic peaks at 243 and 264 nm, in 100 mM K+ (Fig. 1b)[37]
To understand which DNA damage response (DDR) pathway is active in zuo1Δ rad4Δ, we examined the binding of Rad[50] (HR), Ku70 (NHEJ) and Rev[1] (TLS) in zuo1Δ rad4Δ cells

Summary

Introduction

Nucleic acids can fold into G-quadruplex (G4) structures that can fine-tune biological processes. BRCA1 and Rad[51], as well as Ku80, have been shown to interact with G4 structures and function during either homologous recombination (HR) or non-homologous end-joining (NHEJ), respectively[25,26] In addition to these canonical repair pathways, post-replicative repair proteins such as the translesion synthesis (TLS) protein Rev[127,29,30] and the polymerase θ31 have been linked to G4 structure formation. The helicases XPD and XPB, involved in transcription regulation and nucleotide excision repair (NER), have been shown to regulate G4 structures both in vitro and in vivo[32]. These studies underline the finding that G4 structures are prone to breakage and are a risk for genome stability. Zuo[1] modulates G4 structure levels and acts as a molecular switch for the selection of the appropriate DNA repair pathway

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