Publication

RNase H and Postreplication Repair Protect Cells from Ribonucleotides Incorporated in DNA

Lazzaro, F., Novarina, D., Amara, F., Watt, D. L., Stone, J. E., Costanzo, V., Burgers, P. M., Kunkel, T. A., Plevani, P. & Muzi-Falconil, M., 13-Jan-2012, In : Molecular Cell. 45, 1, p. 99-110 12 p.

Research output: Contribution to journalArticleAcademicpeer-review

  • Federico Lazzaro
  • Daniele Novarina
  • Flavio Amara
  • Danielle L. Watt
  • Jana E. Stone
  • Vincenzo Costanzo
  • Peter M. Burgers
  • Thomas A. Kunkel
  • Paolo Plevani
  • Marco Muzi-Falconil

The chemical identity and integrity of the genome is challenged by the incorporation of ribonucleoside triphosphates (rNTPs) in place of deoxyribonucleoside triphosphates (dNTPs) during replication. Misincorporation is limited by the selectivity of DNA replicases. We show that accumulation of ribonucleoside monophosphates (rNMPs) in the genome causes replication stress and has toxic consequences, particularly in the absence of RNase H1 and RNase H2, which remove rNMPs. We demonstrate that postreplication repair (PAR) pathways MMS2-dependent template switch and Pol zeta-dependent bypass are crucial for tolerating the presence of rNMPs in the chromosomes; indeed, we show that Pol efficiently replicates over 1-4 rNMPs. Moreover, cells lacking RNase H accumulate mono- and polyu-biquitylated PCNA and have a constitutively activated PRR. Our findings describe a crucial function for RNase H1, RNase H2, template switch, and translesion DNA synthesis in overcoming rNTPs misincorporated during DNA replication, and may be relevant for the pathogenesis of Aicardi-Goutieres syndrome.

Original languageEnglish
Pages (from-to)99-110
Number of pages12
JournalMolecular Cell
Volume45
Issue number1
Publication statusPublished - 13-Jan-2012
Externally publishedYes

    Keywords

  • AICARDI-GOUTIERES-SYNDROME, YEAST REPLICATIVE POLYMERASES, SACCHAROMYCES-CEREVISIAE, CRYSTAL-STRUCTURE, TRANSLESION SYNTHESIS, TOPOISOMERASE-I, DAMAGE, ZETA, SPECIFICITY, INSTABILITY

ID: 24009618