Format

Send to

Choose Destination
Cell Rep. 2018 Oct 30;25(5):1135-1145.e5. doi: 10.1016/j.celrep.2018.10.019.

Two RNase H2 Mutants with Differential rNMP Processing Activity Reveal a Threshold of Ribonucleotide Tolerance for Embryonic Development.

Author information

1
SFR, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA.
2
NCBI, National Library of Medicine, Bethesda, MD, USA.
3
Mouse Core, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA.
4
SFR, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA. Electronic address: crouchr@mail.nih.gov.

Abstract

RNase H2 has two distinct functions: initiation of the ribonucleotide excision repair (RER) pathway by cleaving ribonucleotides (rNMPs) incorporated during DNA replication and processing the RNA portion of an R-loop formed during transcription. An RNase H2 mutant lacking RER activity but supporting R-loop removal revealed that rNMPs in DNA initiate p53-dependent DNA damage response and early embryonic arrest in mouse. However, an RNase H2 AGS-related mutant with residual RER activity develops to birth. Estimations of the number of rNMPs in DNA in these two mutants define a ribonucleotide threshold above which p53 induces apoptosis. Below the threshold, rNMPs in DNA trigger an innate immune response. Compound heterozygous cells, containing both defective enzymes, retain rNMPs above the threshold, indicative of competition for RER substrates between active and inactive enzymes, suggesting that patients with compound heterozygous mutations in RNASEH2 genes may not reflect the properties of recombinantly expressed proteins.

KEYWORDS:

AGS; Aicardi-Goutières syndrome; DNA damage; RNase H2; embedded ribonucleotides; genome integrity; innate immunity; mouse development; p53 damage response; ribonuclease H2

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center