title: Disruption of Supv3L1 damages the skin and causes sarcopenia, loss of fat, and death.
abstract: Supv3L1 is a conserved and ubiquitously expressed helicase found in numerous tissues and cell types of many species. In human cells, SUPV3L1 was shown to suppress apoptotic death and sister chromatid exchange, and impair mitochondrial RNA metabolism and protein synthesis. In vitro experiments revealed binding of SUPV3L1 to BLM and WRN proteins, suggesting a role in genome maintenance processes. Disruption of the Supv3L1 gene in the mouse has been reported to be embryonic lethal at early developmental stages. We generated a conditional mouse in which the phenotypes associated with the removal of exon 14 can be tested in a variety of tissues. Disruption mediated by a Mx1 promoter-driven Cre displayed a postnatal growth delay, reduced lifespan, loss of adipose tissue and muscle mass, and severe skin abnormalities manifesting as ichthyosis, thickening of the epidermis, and atrophy of the dermis and subcutaneous tissue. Using a tamoxifen-activatable Esr1/Cre driver, Supv3L1 disruption resulted in growth retardation and aging phenotypes, including loss of adipose tissue and muscle mass, kyphosis, cachexia, and premature death. Many of the abnormalities seen in the Mx1-Cre mice, such as hyperkeratosis characterized by profound scaling of feet and tail, could also be detected in tamoxifen-inducible Cre mice. Conditional ablation of Supv3L1 in keratinocytes confirmed atrophic changes in the skin and ichthyosis-like changes. Together, these data indicate that Supv3L1 is important for the maintenance of the skin barrier. In addition, loss of Supv3L1 function leads to accelerated aging-like phenotypes.
authors.affiliation: Division of Biology and Medicine, Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, 70 Ship St., Providence, RI 02903, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Paul
authors.forename: Rachel
authors.initials: R
authors.lastname: Cronan
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Weston
authors.forename: Kim
authors.initials: K
authors.lastname: Boekelheide
authors.forename: John M
authors.initials: JM
authors.lastname: Sedivy
authors.forename: Sang-Yun
authors.initials: SY
authors.lastname: Lee
authors.forename: David L
authors.initials: DL
authors.lastname: Wiest
authors.forename: Murray B
authors.initials: MB
authors.lastname: Resnick
authors.forename: Jan E
authors.initials: JE
authors.lastname: Klysik
mesh_terms: D000273:Adipose Tissue / Q000002:abnormalities* / Q000196:embryology / Q000254:growth & development; D019588:Aging, Premature / Q000235:genetics; D000818:Animals; D002100:Cachexia / Q000235:genetics; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000502:physiology*; D004817:Epidermis / Q000196:embryology / Q000254:growth & development / Q000473:pathology; D006801:Humans; D007057:Ichthyosis / Q000235:genetics; D007738:Kyphosis / Q000235:genetics; D008136:Longevity / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000002:abnormalities; D012867:Skin / Q000196:embryology / Q000254:growth & development / Q000473:pathology; D012868:Skin Abnormalities / Q000235:genetics / Q000473:pathology*; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D013629:Tamoxifen; C542133:Supv3L1 protein, mouse; D053487:DEAD-box RNA Helicases