Reduction of hRNase H2 activity in Aicardi-Goutières syndrome cells leads to replication stress and genome instability.

Abstract

Aicardi-Goutières syndrome (AGS) is an inflammatory encephalopathy caused by defective nucleic acids metabolism. Over 50% of AGS mutations affect RNase H2 the only enzyme able to remove single ribonucleotide-monophosphates (rNMPs) embedded in DNA. Ribonucleotide triphosphates (rNTPs) are incorporated into genomic DNA with relatively high frequency during normal replication making DNA more susceptible to strand breakage and mutations. Here we demonstrate that human cells depleted of RNase H2 show impaired cell cycle progression associated with chronic activation of post-replication repair (PRR) and genome instability. We identify a similar phenotype in cells derived from AGS patients, which indeed accumulate rNMPs in genomic DNA and exhibit markers of constitutive PRR and checkpoint activation. Our data indicate that in human cells RNase H2 plays a crucial role in correcting rNMPs misincorporation, preventing DNA damage. Such protective function is compromised in AGS patients and may be linked to unscheduled immune responses. These findings may be relevant to shed further light on the mechanisms involved in AGS pathogenesis.

• Authors: Sara Pizzi, Sarah Sertic, Simona Orcesi, Cristina Cereda, Marika Bianchi, Andrew P Jackson, Federico Lazzaro, Paolo Plevani, Marco Muzi-Falconi
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 24 Issue 3 Pg. 649-58 (Feb 01 2015) ISSN: 1460-2083 [Electronic] England
• PMID: 25274781 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2014. Published by Oxford University Press.

Chemical References

• Ribonucleotides
• DNA
• ribonuclease HII
• Ribonuclease H

Topics

• Autoimmune Diseases of the Nervous System (genetics, metabolism, pathology)
• Cell Line
• Cell Proliferation
• DNA (chemistry, genetics)
• DNA Damage
• DNA Repair
• DNA Replication
• Gene Knockdown Techniques
• Genomic Instability
• HeLa Cells
• Humans
• Nervous System Malformations (genetics, metabolism, pathology)
• Ribonuclease H (genetics, metabolism)
• Ribonucleotides (metabolism)