Abstract
Genome instability is a condition characterized by the accumulation of genetic alterations and is a hallmark of cancer cells. To uncover new genes and cellular pathways affecting endogenous DNA damage and genome integrity, we exploited a Synthetic Genetic Array (SGA)-based screen in yeast. Among the positive genes, we identified VID22, reported to be involved in DNA double-strand break repair. vid22Δ cells exhibit increased levels of endogenous DNA damage, chronic DNA damage response activation and accumulate DNA aberrations in sequences displaying high probabilities of forming G-quadruplexes (G4-DNA). If not resolved, these DNA secondary structures can block the progression of both DNA and RNA polymerases and correlate with chromosome fragile sites. Vid22 binds to and protects DNA at G4-containing regions both in vitro and in vivo. Loss of VID22 causes an increase in gross chromosomal rearrangement (GCR) events dependent on G-quadruplex forming sequences. Moreover, 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.
Highlights
DNA molecules are intrinsically unstable [1] and are often damaged by exposure to a variety of endogenous and exogenous genotoxic agents [2]
We find that purified Vid22 is able to bind directly DNA G4-forming sequences in vitro, and that Vid22 is enriched on chromatin at G4-DNA and suppresses chromosomal aberrations at G4-DNA structures
On galactose-containing medium, exhibited reduced fitness, often referred to as synthetic dosage lethality (SDL), when the DDC2-containing plasmid was present compared to controls with the empty vector
Summary
DNA molecules are intrinsically unstable [1] and are often damaged by exposure to a variety of endogenous and exogenous genotoxic agents [2]. When not correctly recognized and repaired, lesions can impede DNA duplication and endanger faithful transmission of the genetic material to the progeny. Eukaryotic cells possess evolutionarily conserved mechanisms that act by handling problems or errors arising during DNA replication, repairing DNA lesions, monitoring chromosome segregation and ensuring proper coordination of all these processes with cell cycle progression [3,4,5,6,7].
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