Ribonucleotides Misincorporated into DNA Act as Strand-Discrimination Signals in Eukaryotic Mismatch Repair

Ghodgaonkar, Medini; Lazzaro, Federico; Olivera-Pimentel, Maite; Artola-Borán, Mariela; Ćejka, Petr; Reijns, Martin A.M.; Jackson, Andrew P.; Plevani, Paolo; Muzi-Falconi, Marco; Jiricny, Josef

doi:10.1016/j.molcel.2013.03.019

Cited by 145 publications

(128 citation statements)

References 39 publications

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“…2), as well as with the ability of ribonucleotide repair-deficient yeast (5,6,10,17) and mice (7,19) to survive and replicate genomes that contain large numbers of ribonucleotides. The fact that ribonucleotides incorporated into the genome by DNA polymerases can be tolerated is consistent with the idea that they can have beneficial signaling functions (4,9,11,12). On the other hand, single ribonucleotides in DNA templates at least partially impede synthesis by RB69 Pol, Pol δ, and Pol e (Fig.…”

Section: Discussionsupporting

confidence: 79%

“…On the beneficial side, two consecutive ribonucleotides in the genome are signals for mating type switching in Schizosaccharomyces pombe (11). In addition, recent evidence suggests that RNase H2-dependent processing of ribonucleotides incorporated into the Saccharomyces cerevisiae genome by Pol e, the primary leading strand replicase, generates a signal that can direct mismatch repair (MMR) to correct replication errors in the nascent leading strand (9,12). Other possible beneficial signaling roles for ribonucleotides have also been considered (4,13).…”

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confidence: 99%

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Structure–function analysis of ribonucleotide bypass by B family DNA replicases

Clausen

Murray

Passer

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Ribonucleotides are frequently incorporated into DNA during replication, they are normally removed, and failure to remove them results in replication stress. This stress correlates with DNA polymerase (Pol) stalling during bypass of ribonucleotides in DNA templates. Here we demonstrate that stalling by yeast replicative Pols δ and e increases as the number of consecutive template ribonucleotides increases from one to four. The homologous bacteriophage RB69 Pol also stalls during ribonucleotide bypass, with a pattern most similar to that of Pol e. Crystal structures of an exonuclease-deficient variant of RB69 Pol corresponding to multiple steps in single ribonucleotide bypass reveal that increased stalling is associated with displacement of Tyr391 and an unpreferred C2´-endo conformation for the ribose. Even less efficient bypass of two consecutive ribonucleotides in DNA correlates with similar movements of Tyr391 and displacement of one of the ribonucleotides along with the primer-strand DNA backbone. These structurefunction studies have implications for cellular signaling by ribonucleotides, and they may be relevant to replication stress in cells defective in ribonucleotide excision repair, including humans suffering from autoimmune disease associated with RNase H2 defects.translesion synthesis | replication stalling | DNA replication

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Section: Discussionsupporting

confidence: 79%

mentioning

confidence: 99%

Structure–function analysis of ribonucleotide bypass by B family DNA replicases

Clausen

Murray

Passer

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Since ribonucleotides are more susceptible to spontaneous cleavage than deoxyribonucleotides (40), loss of RER or the presence of aberrant RER due to Top1 (30) could lead to increased strand breaks and, potentially, genome instability. In S. cerevisiae, RNase H2 defects cause weak mutator and hyperrecombination phenotypes (7,(41)(42)(43)(44)(45), and RNase H2 null mouse cells have increased chromosomal rearrangements and a p53-dependent DNA damage response (40,46). Interestingly, defects in RNase H2, as well as the Trex exonucleases, cause Aicardi-Goutieres syndrome, a neuroautoimmune disease that may result from inflammatory responses to aberrant DNA or RNA structures that accumulate as the result of these defects (10,47).…”

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confidence: 99%

A Saccharomyces cerevisiae RNase H2 Interaction Network Functions To Suppress Genome Instability

Allen-Soltero

Martı́nez

Putnam

et al. 2014

Molecular and Cellular Biology

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Errors during DNA replication are one likely cause of gross chromosomal rearrangements (GCRs). Here, we analyze the role of RNase H2, which functions to process Okazaki fragments, degrade transcription intermediates, and repair misincorporated ribonucleotides, in preventing genome instability. The results demonstrate that rnh203 mutations result in a weak mutator phenotype and cause growth defects and synergistic increases in GCR rates when combined with mutations affecting other DNA metabolism pathways, including homologous recombination (HR), sister chromatid HR, resolution of branched HR intermediates, postreplication repair, sumoylation in response to DNA damage, and chromatin assembly. In some cases, a mutation in RAD51 or TOP1 suppressed the increased GCR rates and/or the growth defects of rnh203⌬ double mutants. This analysis suggests that cells with RNase H2 defects have increased levels of DNA damage and depend on other pathways of DNA metabolism to overcome the deleterious effects of this DNA damage.

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“…8,9 The presence of these single ribonucleotides within DNA act as a strand discrimination signal for mismatch repair of leading strand replication errors. 10,11 Interestingly, removal of these ribonucleotides from DNA is essential for long-term maintenance of genome integrity and development. 9,12 Ribonucleotides within RNA-DNA hybrids are recognized and hydrolyzed by the RNase H enzymes.…”

Section: Introductionmentioning

confidence: 99%