title: 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.affiliation: Dipartimento di Bioscienze, Università degli Studi di Milano, 20133 Milano, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Pizzi
authors.affiliation: Dipartimento di Bioscienze, Università degli Studi di Milano, 20133 Milano, Italy.
authors.forename: Sarah
authors.initials: S
authors.lastname: Sertic
authors.affiliation: Child Neurology and Psychiatry Unit.
authors.forename: Simona
authors.initials: S
authors.lastname: Orcesi
authors.affiliation: Laboratory of Experimental Neurobiology, C. Mondino National Neurological Institute, Pavia, Italy and.
authors.forename: Cristina
authors.initials: C
authors.lastname: Cereda
authors.affiliation: Laboratory of Experimental Neurobiology, C. Mondino National Neurological Institute, Pavia, Italy and.
authors.forename: Marika
authors.initials: M
authors.lastname: Bianchi
authors.affiliation: Medical Research Council Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Jackson
authors.affiliation: Dipartimento di Bioscienze, Università degli Studi di Milano, 20133 Milano, Italy marco.muzifalconi@unimi.it paolo.plevani@unimi.it federico.lazzaro@unimi.it.
authors.forename: Federico
authors.initials: F
authors.lastname: Lazzaro
authors.affiliation: Dipartimento di Bioscienze, Università degli Studi di Milano, 20133 Milano, Italy marco.muzifalconi@unimi.it paolo.plevani@unimi.it federico.lazzaro@unimi.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Plevani
authors.affiliation: Dipartimento di Bioscienze, Università degli Studi di Milano, 20133 Milano, Italy marco.muzifalconi@unimi.it paolo.plevani@unimi.it federico.lazzaro@unimi.it.
authors.forename: Marco
authors.initials: M
authors.lastname: Muzi-Falconi
mesh_terms: D020274:Autoimmune Diseases of the Nervous System / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D049109:Cell Proliferation; D004247:DNA / Q000737:chemistry* / Q000235:genetics; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D055785:Gene Knockdown Techniques; D042822:Genomic Instability; D006367:HeLa Cells; D006801:Humans; D009421:Nervous System Malformations / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016914:Ribonuclease H / Q000235:genetics / Q000378:metabolism*; D012265:Ribonucleotides / Q000378:metabolism
chemical_list: D012265:Ribonucleotides; D004247:DNA; C091139:ribonuclease HII; D016914:Ribonuclease H