Genetic requirements for repair of lesions caused by single genomic ribonucleotides in S phase

Natalie Schindler (), Matthias Tonn, Vanessa Kellner, Jia Jun Fung, Arianna Lockhart, Olga Vydzhak, Thomas Juretschke, Stefanie Möckel, Petra Beli, Anton Khmelinskii and Brian Luke ()
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Natalie Schindler: Johannes Gutenberg University Mainz, Institute for Developmental Neurology (IDN), Biozentrum 1
Matthias Tonn: Johannes Gutenberg University Mainz, Institute for Developmental Neurology (IDN), Biozentrum 1
Vanessa Kellner: Institute of Molecular Biology (IMB)
Jia Jun Fung: Institute of Molecular Biology (IMB)
Arianna Lockhart: Institute of Molecular Biology (IMB)
Olga Vydzhak: Johannes Gutenberg University Mainz, Institute for Developmental Neurology (IDN), Biozentrum 1
Thomas Juretschke: Institute of Molecular Biology (IMB)
Stefanie Möckel: Institute of Molecular Biology (IMB)
Petra Beli: Institute of Molecular Biology (IMB)
Anton Khmelinskii: Institute of Molecular Biology (IMB)
Brian Luke: Johannes Gutenberg University Mainz, Institute for Developmental Neurology (IDN), Biozentrum 1

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Single ribonucleoside monophosphates (rNMPs) are transiently present in eukaryotic genomes. The RNase H2-dependent ribonucleotide excision repair (RER) pathway ensures error-free rNMP removal. In some pathological conditions, rNMP removal is impaired. If these rNMPs hydrolyze during, or prior to, S phase, toxic single-ended double-strand breaks (seDSBs) can occur upon an encounter with replication forks. How such rNMP-derived seDSB lesions are repaired is unclear. We expressed a cell cycle phase restricted allele of RNase H2 to nick at rNMPs in S phase and study their repair. Although Top1 is dispensable, the RAD52 epistasis group and Rtt101Mms1-Mms22 dependent ubiquitylation of histone H3 become essential for rNMP-derived lesion tolerance. Consistently, loss of Rtt101Mms1-Mms22 combined with RNase H2 dysfunction leads to compromised cellular fitness. We refer to this repair pathway as nick lesion repair (NLR). The NLR genetic network may have important implications in the context of human pathologies.

Date: 2023
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DOI: 10.1038/s41467-023-36866-6

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