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Determinants of G quadruplex-induced epigenetic instability in REV1-deficient cells.

ABSTRACT: REV1-deficient chicken DT40 cells are compromised in replicating G quadruplex (G4)-forming DNA. This results in localised, stochastic loss of parental chromatin marks and changes in gene expression. We previously proposed that this epigenetic instability arises from G4-induced replication fork stalls disrupting the accurate propagation of chromatin structure through replication. Here, we test this model by showing that a single G4 motif is responsible for the epigenetic instability of the BU-1 locus in REV1-deficient cells, despite its location 3.5 kb from the transcription start site (TSS). The effect of the G4 is dependent on it residing on the leading strand template, but is independent of its in vitro thermal stability. Moving the motif to more than 4 kb from the TSS stabilises expression of the gene. However, loss of histone modifications (H3K4me3 and H3K9/14ac) around the transcription start site correlates with the position of the G4 motif, expression being lost only when the promoter is affected. This supports the idea that processive replication is required to maintain the histone modification pattern and full transcription of this model locus.

SUBMITTER: Schiavone D

PROVIDER: S-EPMC4282387 | biostudies-literature |

REPOSITORIES: biostudies-literature

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VID22 counteracts G-quadruplex-induced genome instability.

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Human Rev1 polymerase disrupts G-quadruplex DNA.

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VID22 counteracts G-quadruplex-induced genome instability

Project description:Genome instability is a condition characterized by the accumulation of various genetic alterations and is a hallmark of cancer cells. To uncover new genes and cellular pathways controlling the levels of endogenous DNA damage and affecting genome integrity, we exploited a Synthetic Genetic Array (SGA)-based screen in yeast. Among the positive genes, we identified VID22, a gene previously reported to be involved in DNA double-strand break repair. We found that vid22Δ cells exhibit chronic DNA damage response activation, show increased levels of increased endogenous DNA damage and accumulate DNA aberrations in sequences displaying high probabilities of forming G-quadruplexes (G4-DNA). If not resolved, these non-canonical DNA secondary structures can block the progression of both DNA and RNA polymerases and correlate with chromosome fragile sites. We show that Vid22 in vitro and in vivo binds directly to and protects DNA at G4-containing regions both in vitro and in vivo. In particular, loss of VID22 causes an increase in gross chromosomal rearrangement (GCR) events dependent on G-quadruplex forming sequences. We also demonstrate that the absence of Vid22 causes defects in the correct maintenance of G4-DNA rich elements, such as telomeres and mtDNA, and hypersensitivity to the G4-stabilizing ligand TMPyP4. We thus propose that Vid22 is directly involved in genome integrity maintenance as a novel regulator of G4 metabolism.

2021-11-08 | GSE174688 | GEO

Hydrogen peroxide induced genomic instability in nucleotide excision repair-deficient lymphoblastoid cells.

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Local epigenetic reprogramming induced by G-quadruplex ligands.

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VID22 counteracts G-quadruplex-induced genome instability

Project description:VID22 counteracts G-quadruplex-induced genome instability

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