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

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

doi:10.1038/s41467-020-17701-8

Cited by 28 publications

(23 citation statements)

References 86 publications

(122 reference statements)

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“…Yet, in spite of a clear role for TLS pols in G4 replication, there are aspects of this function that continue to be clarified. This was recently illustrated by the finding that Zuo1 blocks Rev1 binding to G4s that form near UV damage, favouring nucleotide excision repair of the UV-induced lesion ( 53 ). The Y-family members pols η and κ participate in prevention of G4-induced genomic instability ( 54 ).…”

Section: Discussionmentioning

confidence: 99%

Human Rev1 relies on insert-2 to promote selective binding and accurate replication of stabilized G-quadruplex motifs

Ketkar

Smith

Johnson³

et al. 2021

Nucleic Acids Research

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We previously reported that human Rev1 (hRev1) bound to a parallel-stranded G-quadruplex (G4) from the c-MYC promoter with high affinity. We have extended those results to include other G4 motifs, finding that hRev1 exhibited stronger affinity for parallel-stranded G4 than either anti-parallel or hybrid folds. Amino acids in the αE helix of insert-2 were identified as being important for G4 binding. Mutating E466 and Y470 to alanine selectively perturbed G4 binding affinity. The E466K mutant restored wild-type G4 binding properties. Using a forward mutagenesis assay, we discovered that loss of hRev1 increased G4 mutation frequency >200-fold compared to the control sequence. Base substitutions and deletions occurred around and within the G4 motif. Pyridostatin (PDS) exacerbated this effect, as the mutation frequency increased >700-fold over control and deletions upstream of the G4 site more than doubled. Mutagenic replication of G4 DNA (±PDS) was partially rescued by wild-type and E466K hRev1. The E466A or Y470A mutants failed to suppress the PDS-induced increase in G4 mutation frequency. These findings have implications for the role of insert-2, a motif conserved in vertebrates but not yeast or plants, in Rev1-mediated suppression of mutagenesis during G4 replication.

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Section: Discussionmentioning

confidence: 99%

Human Rev1 relies on insert-2 to promote selective binding and accurate replication of stabilized G-quadruplex motifs

Ketkar

Smith

Johnson³

et al. 2021

Nucleic Acids Research

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“…In addition to the BER-mediated repair of oxidative base damage associated with the formation of G4 structures, oxidative-stress-dependent G4 folding has been shown to affect the nucleotide excision repair (NER) pathway, inducing its activation [ 134 ]. DNA damage caused by reactive oxygen species, followed by the abasic site generation by BER proteins, makes G4 formation more energetically favorable than maintaining a competing DNA duplex structure ( Figure 6 a).…”

Section: G4 Activates the Removal Of Uv-induced Damage By Nucleotide Excision Repairmentioning

confidence: 99%

Impact of G-Quadruplexes on the Regulation of Genome Integrity, DNA Damage and Repair

et al. 2021

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DNA G-quadruplexes (G4s) are known to be an integral part of the complex regulatory systems in both normal and pathological cells. At the same time, the ability of G4s to impede DNA replication plays a critical role in genome integrity. This review summarizes the results of recent studies of G4-mediated genomic and epigenomic instability, together with associated DNA damage and repair processes. Although the underlying mechanisms remain to be elucidated, it is known that, among the proteins that recognize G4 structures, many are linked to DNA repair. We analyzed the possible role of G4s in promoting double-strand DNA breaks, one of the most deleterious DNA lesions, and their repair via error-prone mechanisms. The patterns of G4 damage, with a focus on the introduction of oxidative guanine lesions, as well as their removal from G4 structures by canonical repair pathways, were also discussed together with the effects of G4s on the repair machinery. According to recent findings, there must be a delicate balance between G4-induced genome instability and G4-promoted repair processes. A broad overview of the factors that modulate the stability of G4 structures in vitro and in vivo is also provided here.

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“…We recently performed an in vivo yeast-one hybrid screen and identified novel G4 interacting proteins. We identified over 100 protein candidates including Slx9 and Zuo1 (Gotz et al 2019 ; De Magis et al 2020 ). Their G4-binding was already confirmed in vivo and in vivo.…”

Section: Mgs1 Preserves Genome Stability At the Replication Forkmentioning

confidence: 99%

Mgs1 function at G-quadruplex structures during DNA replication

Paeschke

Burkovics

2020

Curr Genet

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The coordinated action of DNA polymerases and DNA helicases is essential at genomic sites that are hard to replicate. Among these are sites that harbour G-quadruplex DNA structures (G4). G4s are stable alternative DNA structures, which have been implicated to be involved in important cellular processes like the regulation of gene expression or telomere maintenance. G4 structures were shown to hinder replication fork progression and cause genomic deletions, mutations and recombination events. Many helicases unwind G4 structures and preserve genome stability, but a detailed understanding of G4 replication and the re-start of stalled replication forks around formed G4 structures is not clear, yet. In our recent study, we identified that Mgs1 preferentially binds to G4 DNA structures in vitro and is associated with putative G4-forming chromosomal regions in vivo. Mgs1 binding to G4 motifs in vivo is partially dependent on the helicase Pif1. Pif1 is the major G4-unwinding helicase in S. cerevisiae. In the absence of Mgs1, we determined elevated gross chromosomal rearrangement (GCR) rates in yeast, similar to Pif1 deletion. Here, we highlight the recent findings and set these into context with a new mechanistic model. We propose that Mgs1's functions support DNA replication at G4-forming regions.

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

Cited by 28 publications

References 86 publications

Human Rev1 relies on insert-2 to promote selective binding and accurate replication of stabilized G-quadruplex motifs

Human Rev1 relies on insert-2 to promote selective binding and accurate replication of stabilized G-quadruplex motifs

Impact of G-Quadruplexes on the Regulation of Genome Integrity, DNA Damage and Repair

Mgs1 function at G-quadruplex structures during DNA replication

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