Cell-autonomous progeroid changes in conditional mouse models for repair endonuclease XPG deficiency.
As part of the Nucleotide Excision Repair (NER) process, the endonuclease XPG is involved in repair of helix-distorting DNA lesions, but the protein has also been implicated in several other DNA repair systems, complicating genotype-phenotype relationship in XPG patients. Defects in XPG can cause ei...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2014-10-01
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| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC4191938?pdf=render |
| _version_ | 1818307393429176320 |
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| author | Sander Barnhoorn Lieneke M Uittenboogaard Dick Jaarsma Wilbert P Vermeij Maria Tresini Michael Weymaere Hervé Menoni Renata M C Brandt Monique C de Waard Sander M Botter Altaf H Sarker Nicolaas G J Jaspers Gijsbertus T J van der Horst Priscilla K Cooper Jan H J Hoeijmakers Ingrid van der Pluijm |
| author_facet | Sander Barnhoorn Lieneke M Uittenboogaard Dick Jaarsma Wilbert P Vermeij Maria Tresini Michael Weymaere Hervé Menoni Renata M C Brandt Monique C de Waard Sander M Botter Altaf H Sarker Nicolaas G J Jaspers Gijsbertus T J van der Horst Priscilla K Cooper Jan H J Hoeijmakers Ingrid van der Pluijm |
| author_sort | Sander Barnhoorn |
| collection | DOAJ |
| description | As part of the Nucleotide Excision Repair (NER) process, the endonuclease XPG is involved in repair of helix-distorting DNA lesions, but the protein has also been implicated in several other DNA repair systems, complicating genotype-phenotype relationship in XPG patients. Defects in XPG can cause either the cancer-prone condition xeroderma pigmentosum (XP) alone, or XP combined with the severe neurodevelopmental disorder Cockayne Syndrome (CS), or the infantile lethal cerebro-oculo-facio-skeletal (COFS) syndrome, characterized by dramatic growth failure, progressive neurodevelopmental abnormalities and greatly reduced life expectancy. Here, we present a novel (conditional) Xpg-/- mouse model which -in a C57BL6/FVB F1 hybrid genetic background- displays many progeroid features, including cessation of growth, loss of subcutaneous fat, kyphosis, osteoporosis, retinal photoreceptor loss, liver aging, extensive neurodegeneration, and a short lifespan of 4-5 months. We show that deletion of XPG specifically in the liver reproduces the progeroid features in the liver, yet abolishes the effect on growth or lifespan. In addition, specific XPG deletion in neurons and glia of the forebrain creates a progressive neurodegenerative phenotype that shows many characteristics of human XPG deficiency. Our findings therefore exclude that both the liver as well as the neurological phenotype are a secondary consequence of derailment in other cell types, organs or tissues (e.g. vascular abnormalities) and support a cell-autonomous origin caused by the DNA repair defect itself. In addition they allow the dissection of the complex aging process in tissue- and cell-type-specific components. Moreover, our data highlight the critical importance of genetic background in mouse aging studies, establish the Xpg-/- mouse as a valid model for the severe form of human XPG patients and segmental accelerated aging, and strengthen the link between DNA damage and aging. |
| first_indexed | 2024-12-13T06:57:40Z |
| format | Article |
| id | doaj.art-2627a48029944382a7b41ce43b35c0ba |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-13T06:57:40Z |
| publishDate | 2014-10-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-2627a48029944382a7b41ce43b35c0ba2022-12-21T23:56:01ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042014-10-011010e100468610.1371/journal.pgen.1004686Cell-autonomous progeroid changes in conditional mouse models for repair endonuclease XPG deficiency.Sander BarnhoornLieneke M UittenboogaardDick JaarsmaWilbert P VermeijMaria TresiniMichael WeymaereHervé MenoniRenata M C BrandtMonique C de WaardSander M BotterAltaf H SarkerNicolaas G J JaspersGijsbertus T J van der HorstPriscilla K CooperJan H J HoeijmakersIngrid van der PluijmAs part of the Nucleotide Excision Repair (NER) process, the endonuclease XPG is involved in repair of helix-distorting DNA lesions, but the protein has also been implicated in several other DNA repair systems, complicating genotype-phenotype relationship in XPG patients. Defects in XPG can cause either the cancer-prone condition xeroderma pigmentosum (XP) alone, or XP combined with the severe neurodevelopmental disorder Cockayne Syndrome (CS), or the infantile lethal cerebro-oculo-facio-skeletal (COFS) syndrome, characterized by dramatic growth failure, progressive neurodevelopmental abnormalities and greatly reduced life expectancy. Here, we present a novel (conditional) Xpg-/- mouse model which -in a C57BL6/FVB F1 hybrid genetic background- displays many progeroid features, including cessation of growth, loss of subcutaneous fat, kyphosis, osteoporosis, retinal photoreceptor loss, liver aging, extensive neurodegeneration, and a short lifespan of 4-5 months. We show that deletion of XPG specifically in the liver reproduces the progeroid features in the liver, yet abolishes the effect on growth or lifespan. In addition, specific XPG deletion in neurons and glia of the forebrain creates a progressive neurodegenerative phenotype that shows many characteristics of human XPG deficiency. Our findings therefore exclude that both the liver as well as the neurological phenotype are a secondary consequence of derailment in other cell types, organs or tissues (e.g. vascular abnormalities) and support a cell-autonomous origin caused by the DNA repair defect itself. In addition they allow the dissection of the complex aging process in tissue- and cell-type-specific components. Moreover, our data highlight the critical importance of genetic background in mouse aging studies, establish the Xpg-/- mouse as a valid model for the severe form of human XPG patients and segmental accelerated aging, and strengthen the link between DNA damage and aging.http://europepmc.org/articles/PMC4191938?pdf=render |
| spellingShingle | Sander Barnhoorn Lieneke M Uittenboogaard Dick Jaarsma Wilbert P Vermeij Maria Tresini Michael Weymaere Hervé Menoni Renata M C Brandt Monique C de Waard Sander M Botter Altaf H Sarker Nicolaas G J Jaspers Gijsbertus T J van der Horst Priscilla K Cooper Jan H J Hoeijmakers Ingrid van der Pluijm Cell-autonomous progeroid changes in conditional mouse models for repair endonuclease XPG deficiency. PLoS Genetics |
| title | Cell-autonomous progeroid changes in conditional mouse models for repair endonuclease XPG deficiency. |
| title_full | Cell-autonomous progeroid changes in conditional mouse models for repair endonuclease XPG deficiency. |
| title_fullStr | Cell-autonomous progeroid changes in conditional mouse models for repair endonuclease XPG deficiency. |
| title_full_unstemmed | Cell-autonomous progeroid changes in conditional mouse models for repair endonuclease XPG deficiency. |
| title_short | Cell-autonomous progeroid changes in conditional mouse models for repair endonuclease XPG deficiency. |
| title_sort | cell autonomous progeroid changes in conditional mouse models for repair endonuclease xpg deficiency |
| url | http://europepmc.org/articles/PMC4191938?pdf=render |
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