4.8 Article

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

Journal

NUCLEIC ACIDS RESEARCH
Volume 47, Issue 9, Pages 4612-4623

Publisher

OXFORD UNIV PRESS
DOI: 10.1093/nar/gkz165

Keywords

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Funding

  1. Associazione Italiana per la Ricerca sul Cancro [15631, 21806, 15724]
  2. MIUR
  3. Telethon [GGP15227]
  4. Fondazione Cariplo [15724, 2013-0798]
  5. Fondazione Telethon [GGP15227]

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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 eta (Pol eta) plays a role in DNA replication under low deoxyribonucleotides condition triggered by hydroxyurea. In particular, the catalytic reaction performed by Pol eta is detrimental for RNase H deficient cells, causing DNA damage checkpoint activation and G2/M arrest. Moreover, a Pol eta 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 eta 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.

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