title: Neil2-null Mice Accumulate Oxidized DNA Bases in the Transcriptionally Active Sequences of the Genome and Are Susceptible to Innate Inflammation.
abstract: Why mammalian cells possess multiple DNA glycosylases (DGs) with overlapping substrate ranges for repairing oxidatively damaged bases via the base excision repair (BER) pathway is a long-standing question. To determine the biological role of these DGs, null animal models have been generated. Here, we report the generation and characterization of mice lacking Neil2 (Nei-like 2). As in mice deficient in each of the other four oxidized base-specific DGs (OGG1, NTH1, NEIL1, and NEIL3), Neil2-null mice show no overt phenotype. However, middle-aged to old Neil2-null mice show the accumulation of oxidative genomic damage, mostly in the transcribed regions. Immuno-pulldown analysis from wild-type (WT) mouse tissue showed the association of NEIL2 with RNA polymerase II, along with Cockayne syndrome group B protein, TFIIH, and other BER proteins. Chromatin immunoprecipitation analysis from mouse tissue showed co-occupancy of NEIL2 and RNA polymerase II only on the transcribed genes, consistent with our earlier in vitro findings on NEIL2's role in transcription-coupled BER. This study provides the first in vivo evidence of genomic region-specific repair in mammals. Furthermore, telomere loss and genomic instability were observed at a higher frequency in embryonic fibroblasts from Neil2-null mice than from the WT. Moreover, Neil2-null mice are much more responsive to inflammatory agents than WT mice. Taken together, our results underscore the importance of NEIL2 in protecting mammals from the development of various pathologies that are linked to genomic instability and/or inflammation. NEIL2 is thus likely to play an important role in long term genomic maintenance, particularly in long-lived mammals such as humans.
authors.affiliation: From the Department of Internal Medicine, Sealy Center for Molecular Medicine.
authors.forename: Anirban
authors.initials: A
authors.lastname: Chakraborty
authors.affiliation: Departments of Neurology and Neuroscience and Cell Biology, Transgenic Mouse Core Facility, University of Texas Medical Branch, Galveston, Texas 77555.
authors.forename: Maki
authors.initials: M
authors.lastname: Wakamiya
authors.affiliation: From the Department of Internal Medicine, Sealy Center for Molecular Medicine.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Venkova-Canova
authors.affiliation: the Department of Radiation Oncology, Houston Methodist Research Institute, Houston, Texas 77030, and.
authors.forename: Raj K
authors.initials: RK
authors.lastname: Pandita
authors.affiliation: Microbiology and Immunology, and.
authors.forename: Leopoldo
authors.initials: L
authors.lastname: Aguilera-Aguirre
authors.affiliation: the Department of Cancer and DNA Damage Responses, Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720.
authors.forename: Altaf H
authors.initials: AH
authors.lastname: Sarker
authors.affiliation: the Department of Radiation Oncology, Houston Methodist Research Institute, Houston, Texas 77030, and.
authors.forename: Dharmendra Kumar
authors.initials: DK
authors.lastname: Singh
authors.affiliation: From the Department of Internal Medicine, Sealy Center for Molecular Medicine.
authors.forename: Koa
authors.initials: K
authors.lastname: Hosoki
authors.affiliation: Biochemistry and Molecular Biology, and.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Wood
authors.affiliation: From the Department of Internal Medicine, Sealy Center for Molecular Medicine.
authors.forename: Gulshan
authors.initials: G
authors.lastname: Sharma
authors.affiliation: From the Department of Internal Medicine, Sealy Center for Molecular Medicine.
authors.forename: Victor
authors.initials: V
authors.lastname: Cardenas
authors.affiliation: Departments of Neurology and Neuroscience and Cell Biology.
authors.forename: Partha S
authors.initials: PS
authors.lastname: Sarkar
authors.affiliation: From the Department of Internal Medicine, Sealy Center for Molecular Medicine.
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Sur
authors.affiliation: the Department of Radiation Oncology, Houston Methodist Research Institute, Houston, Texas 77030, and.
authors.forename: Tej K
authors.initials: TK
authors.lastname: Pandita
authors.affiliation: Microbiology and Immunology, and.
authors.forename: Istvan
authors.initials: I
authors.lastname: Boldogh
authors.affiliation: From the Department of Internal Medicine, Sealy Center for Molecular Medicine, tkhazra@utmb.edu.
authors.forename: Tapas K
authors.initials: TK
authors.lastname: Hazra
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D045647:DNA Glycosylases / Q000172:deficiency* / Q000235:genetics*; D055786:Gene Knockout Techniques; D016678:Genome / Q000235:genetics*; D042822:Genomic Instability; D006706:Homeostasis; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D051379:Mice; D010084:Oxidation-Reduction; D012319:RNA Polymerase II / Q000378:metabolism; D016615:Telomere / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D004247:DNA; D012319:RNA Polymerase II; D045647:DNA Glycosylases; C502613:Neil2 protein, mouse
keywords: DNA damage; DNA damage and repair; DNA enzyme; DNA glycosylase; NEIL2; gene knockout; inflammation; knock-out animals; reactive oxygen species; transcription-coupled repair