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.

VID22 counteracts G-quadruplex-induced genome instability / E. Galati, M.C. Bosio, D. Novarina, M. Chiara, G.M. Bernini, A.M. Mozzarelli, M.L. Garcia-Rubio, B. Gomez-Gonzalez, A. Aguilera, T. Carzaniga, M. Todisco, T. Bellini, G.M. Nava, G. Frige, S. Sertic, D.S. Horner, A. Baryshnikova, C. Manzari, A.M. D'Erchia, G. Pesole, G.W. Brown, M. Muzi-Falconi, F. Lazzaro. - In: NUCLEIC ACIDS RESEARCH. - ISSN 1362-4962. - 49:22(2021 Dec 16), pp. 12785-12804. [10.1093/nar/gkab1156]

VID22 counteracts G-quadruplex-induced genome instability

E. Galati
Primo
;
M.C. Bosio
Secondo
;
D. Novarina;M. Chiara;G.M. Bernini;T. Carzaniga;M. Todisco;T. Bellini;G.M. Nava;S. Sertic;D.S. Horner;G. Pesole;M. Muzi-Falconi
Penultimo
;
F. Lazzaro
Ultimo
2021-12-16

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.
Chromosome Aberrations; DNA Damage; Genome, Fungal; Membrane Proteins; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Telomere Homeostasis; G-Quadruplexes; Genomic Instability
Settore BIO/11 - Biologia Molecolare
PRIN201517MMUZI - ATR and ATM-mediated control of chromosome integrity and cell plasticity - MUZI FALCONI, MARCO - PRIN2015 - PRIN bando 2015 - 2017
PRIN201719MMUZI_01 - G quadruplexes as modulators of genome stability - MUZI FALCONI, MARCO - PRIN2017 - PRIN bando 2017 - 2019
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/902386
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