Ribonuclease H (RNase H) are evolutionary conserved enzymes that cleave the RNA moiety in RNA:DNA hybrid molecules. It has been found that replicative DNA polymerases can incorporate rNTPs in place of dNTPs during DNA replication with an unexpected high frequency (McElhinny et al., 2010a; 2010b). The high rate of rNTPs mis-incorporation observed under normal conditions suggests physiological functions for rNMPs in newly replicated DNA. I was recently demonstrated that the incorporation of rNMPs during leading strand DNA synthesis acts as a strand discrimination signal for the Mismatch DNA repair machinery (Ghodgaonkar et al., 2013; Lujan et al., 2013); moreover, rNMPs embedded in chromosomal DNA can represent an imprint, positioned in S-phase, that regulates DNA transactions (Dalgaard, 2012). RNase H enzymes are crucial for the removal of these rNMPs from genomic DNA and for the maintenance of chromosome integrity. Recently we have found that impairment of RNase H activity in yeast and human causes rNMPs accumulation in the genome and chronic activation of the post-replication repair (PRR) system, which becomes essential for cell survival (Lazzaro et al., 2012; Pizzi et al. in revision). Here, we focus on the contribution of the three different TLS Polymerases (Rev1, Pol ζ and Pol η) to genomic-rNMPs tolerance in budding yeast. We observed that TLS polymerases not only have an important role in bypassing unrepaired-rNMPs in the genome, but they can also incorporate rNMPs during DNA replication. In particular the evolutionary conserved TLS polymerase Pol-η shows elevated predisposition to mis-incorporate rNMPs when the dNTPs pools are limited, while Rev1 counteracts this function avoiding the excess incorporation of rNMPs during DNA replication, preserving genome integrity.

Role of Translesion Synthesis (TLS) polymerases in rNMPs incorporation during DNA replication / D. Delmastro, A. Meroni, S. Pizzi, S. Sertic, P.M.J. Burger, T.A. Kunkel, P. Plevani, M. Muzi Falconi, F. Lazzaro. ((Intervento presentato al convegno RNase tenutosi a Warrenton nel 2014.

Role of Translesion Synthesis (TLS) polymerases in rNMPs incorporation during DNA replication

D. Delmastro
Primo
;
A. Meroni
Secondo
;
S. Sertic;P. Plevani
;
M. Muzi Falconi
Penultimo
;
F. Lazzaro
Ultimo
2014

Abstract

Ribonuclease H (RNase H) are evolutionary conserved enzymes that cleave the RNA moiety in RNA:DNA hybrid molecules. It has been found that replicative DNA polymerases can incorporate rNTPs in place of dNTPs during DNA replication with an unexpected high frequency (McElhinny et al., 2010a; 2010b). The high rate of rNTPs mis-incorporation observed under normal conditions suggests physiological functions for rNMPs in newly replicated DNA. I was recently demonstrated that the incorporation of rNMPs during leading strand DNA synthesis acts as a strand discrimination signal for the Mismatch DNA repair machinery (Ghodgaonkar et al., 2013; Lujan et al., 2013); moreover, rNMPs embedded in chromosomal DNA can represent an imprint, positioned in S-phase, that regulates DNA transactions (Dalgaard, 2012). RNase H enzymes are crucial for the removal of these rNMPs from genomic DNA and for the maintenance of chromosome integrity. Recently we have found that impairment of RNase H activity in yeast and human causes rNMPs accumulation in the genome and chronic activation of the post-replication repair (PRR) system, which becomes essential for cell survival (Lazzaro et al., 2012; Pizzi et al. in revision). Here, we focus on the contribution of the three different TLS Polymerases (Rev1, Pol ζ and Pol η) to genomic-rNMPs tolerance in budding yeast. We observed that TLS polymerases not only have an important role in bypassing unrepaired-rNMPs in the genome, but they can also incorporate rNMPs during DNA replication. In particular the evolutionary conserved TLS polymerase Pol-η shows elevated predisposition to mis-incorporate rNMPs when the dNTPs pools are limited, while Rev1 counteracts this function avoiding the excess incorporation of rNMPs during DNA replication, preserving genome integrity.
Settore BIO/11 - Biologia Molecolare
Role of Translesion Synthesis (TLS) polymerases in rNMPs incorporation during DNA replication / D. Delmastro, A. Meroni, S. Pizzi, S. Sertic, P.M.J. Burger, T.A. Kunkel, P. Plevani, M. Muzi Falconi, F. Lazzaro. ((Intervento presentato al convegno RNase tenutosi a Warrenton nel 2014.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/251132
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