title: NRMT1 knockout mice exhibit phenotypes associated with impaired DNA repair and premature aging.
abstract: Though defective genome maintenance and DNA repair have long been known to promote phenotypes of premature aging, the role protein methylation plays in these processes is only now emerging. We have recently identified the first N-terminal methyltransferase, NRMT1, which regulates protein-DNA interactions and is necessary for both accurate mitotic division and nucleotide excision repair. To demonstrate if complete loss of NRMT1 subsequently resulted in developmental or aging phenotypes, we constructed the first NRMT1 knockout (Nrmt1(-/-)) mouse. The majority of these mice die shortly after birth. However, the ones that survive, exhibit decreased body size, female-specific infertility, kyphosis, decreased mitochondrial function, and early-onset liver degeneration; phenotypes characteristic of other mouse models deficient in DNA repair. The livers from Nrmt1(-/-) mice produce less reactive oxygen species (ROS) than wild type controls, and Nrmt1(-/-) mouse embryonic fibroblasts show a decreased capacity for handling oxidative damage. This indicates that decreased mitochondrial function may benefit Nrmt1(-/-) mice and protect them from excess internal ROS and subsequent DNA damage. These studies position the NRMT1 knockout mouse as a useful new system for studying the effects of genomic instability and defective DNA damage repair on organismal and tissue-specific aging.
authors.affiliation: Department of Biochemistry & Molecular Genetics, Gheens Center on Aging, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Bonsignore
authors.affiliation: Department of Biochemistry & Molecular Genetics, Gheens Center on Aging, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: John G
authors.initials: JG
authors.lastname: Tooley
authors.affiliation: Department of Biochemistry & Molecular Genetics, Gheens Center on Aging, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Van Hoose
authors.affiliation: Department of Biochemistry & Molecular Genetics, Gheens Center on Aging, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Wang
authors.affiliation: Department of Biochemistry & Molecular Genetics, Gheens Center on Aging, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Cheng
authors.affiliation: Department of Biochemistry & Molecular Genetics, Gheens Center on Aging, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: Marsha P
authors.initials: MP
authors.lastname: Cole
authors.affiliation: Department of Biochemistry & Molecular Genetics, Gheens Center on Aging, University of Louisville School of Medicine, Louisville, KY 40202, USA. Electronic address: cescha05@louisville.edu.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Schaner Tooley
mesh_terms: D019588:Aging, Premature / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D000818:Animals; D004260:DNA Repair; D005260:Female; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D007247:Infertility, Female / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008780:Methyltransferases / Q000172:deficiency*; D051379:Mice; D018345:Mice, Knockout; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D008780:Methyltransferases
keywords: Aging; DNA repair; Mitochondria; N-terminal methylation
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