RNA:DNA hybrids are transient physiological intermediates that arise during several cellular processes such as DNA replication. In pathological situations, they may stably accumulate and pose a threat to genome integrity. Cellular RNase H activities process these structures to restore the correct DNA:DNA sequence. Yeast cells lacking RNase H are negatively affected by depletion of deoxyribonucleotide pools necessary for DNA replication. Here we show that the translesion synthesis DNA polymerase (Pol ) plays a role in DNA replication under low deoxyribonucleotides condition triggered by hydroxyurea. In particular, the catalytic reaction performed by Pol is detrimental for RNase H deficient cells, causing DNA damage checkpoint activation and G2/M arrest. Moreover, a Pol mutant allele with enhanced ribonucleotide incorporation further exacerbates the sensitivity to hydroxyurea of cells lacking RNase H activities. Our data are compatible with a model in which Pol activity facilitates the formation or stabilization of RNA:DNA hybrids at stalled replication forks. However, in a scenario where RNase H activity fails to restore DNA, these hybrids become highly toxic for cells.

RNase H activities counteract a toxic effect of Polymerase in cells replicating with depleted dNTP pools / A. Meroni, G.M. Nava, E. Bianco, L. Grasso, E. Galati, M.C. Bosio, D. Dalmastro, M. Muzi Falconi, F. Lazzaro. - In: NUCLEIC ACIDS RESEARCH. - ISSN 1362-4962. - 7:9(2019 May 21), pp. 4612-4623.

RNase H activities counteract a toxic effect of Polymerase in cells replicating with depleted dNTP pools

A. Meroni
Primo
;
G.M. Nava
Secondo
;
E. Bianco;L. Grasso;E. Galati;M.C. Bosio;M. Muzi Falconi
Penultimo
;
F. Lazzaro
Ultimo
2019-05-21

Abstract

RNA:DNA hybrids are transient physiological intermediates that arise during several cellular processes such as DNA replication. In pathological situations, they may stably accumulate and pose a threat to genome integrity. Cellular RNase H activities process these structures to restore the correct DNA:DNA sequence. Yeast cells lacking RNase H are negatively affected by depletion of deoxyribonucleotide pools necessary for DNA replication. Here we show that the translesion synthesis DNA polymerase (Pol ) plays a role in DNA replication under low deoxyribonucleotides condition triggered by hydroxyurea. In particular, the catalytic reaction performed by Pol is detrimental for RNase H deficient cells, causing DNA damage checkpoint activation and G2/M arrest. Moreover, a Pol mutant allele with enhanced ribonucleotide incorporation further exacerbates the sensitivity to hydroxyurea of cells lacking RNase H activities. Our data are compatible with a model in which Pol activity facilitates the formation or stabilization of RNA:DNA hybrids at stalled replication forks. However, in a scenario where RNase H activity fails to restore DNA, these hybrids become highly toxic for cells.
Settore BIO/11 - Biologia Molecolare
Settore BIO/18 - Genetica
feb-2019
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/630073
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