VID22 counteracts G-quadruplex-induced genome instability

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....

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Published in:	Nucleic acids research Vol. 49; no. 22; pp. 12785 - 12804
Main Authors:	Galati, Elena, Bosio, Maria C, Novarina, Daniele, Chiara, Matteo, Bernini, Giulia M, Mozzarelli, Alessandro M, García-Rubio, Maria L, Gómez-González, Belén, Aguilera, Andrés, Carzaniga, Thomas, Todisco, Marco, Bellini, Tommaso, Nava, Giulia M, Frigè, Gianmaria, Sertic, Sarah, Horner, David S, Baryshnikova, Anastasia, Manzari, Caterina, D’Erchia, Anna M, Pesole, Graziano, Brown, Grant W, Muzi-Falconi, Marco, Lazzaro, Federico
Format:	Journal Article
Language:	English
Published:	England Oxford University Press 16-12-2021
Subjects:	Chromosome Aberrations DNA Damage G-Quadruplexes Genome Integrity, Repair and Genome, Fungal Genomic Instability Membrane Proteins - genetics Membrane Proteins - metabolism Membrane Proteins - physiology Saccharomyces cerevisiae - genetics Saccharomyces cerevisiae Proteins - genetics Saccharomyces cerevisiae Proteins - metabolism Saccharomyces cerevisiae Proteins - physiology Telomere Homeostasis
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 The authors wish it to be known that, in their opinion, the first three authors should be regarded as Joint First Authors.
ISSN:	0305-1048 1362-4962
DOI:	10.1093/nar/gkab1156