Senescence induced by RECQL4 dysfunction contributes to Rothmund-Thomson syndrome features in mice.
Cellular senescence refers to irreversible growth arrest of primary eukaryotic cells, a process thought to contribute to aging-related degeneration and disease. Deficiency of RecQ helicase RECQL4 leads to Rothmund-Thomson syndrome (RTS), and we have investigated whether senescence is involved using cellular approaches and a mouse model. We first systematically investigated whether depletion of RECQL4 and the other four human RecQ helicases, BLM, WRN, RECQL1 and RECQL5, impacts the proliferative potential of human primary fibroblasts. BLM-, WRN- and RECQL4-depleted cells display increased staining of senescence-associated β-galactosidase (SA-β-gal), higher expression of p16(INK4a) or/and p21(WAF1) and accumulated persistent DNA damage foci. These features were less frequent in RECQL1- and RECQL5-depleted cells. We have mapped the region in RECQL4 that prevents cellular senescence to its N-terminal region and helicase domain. We further investigated senescence features in an RTS mouse model, Recql4-deficient mice (Recql4(HD)). Tail fibroblasts from Recql4(HD) showed increased SA-β-gal staining and increased DNA damage foci. We also identified sparser tail hair and fewer blood cells in Recql4(HD) mice accompanied with increased senescence in tail hair follicles and in bone marrow cells. In conclusion, dysfunction of RECQL4 increases DNA damage and triggers premature senescence in both human and mouse cells, which may contribute to symptoms in RTS patients.
Laboratory of Molecular Gerontology, Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
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H
Lu
Laboratory of Molecular Gerontology, Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
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EF
Fang
Laboratory of Molecular Gerontology, Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
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P
Sykora
Laboratory of Molecular Gerontology, Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
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Kulikowicz
Gene Expression and Genomics Unit, National Institute on Aging, National Institutes of Health, MD 21224, USA.
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Zhang
Gene Expression and Genomics Unit, National Institute on Aging, National Institutes of Health, MD 21224, USA.
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KG
Becker
Laboratory of Molecular Gerontology, Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
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DL
Croteau
Laboratory of Molecular Gerontology, Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
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VA
Bohr
D000367:Age Factors; D000375:Aging / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells / Q000201:enzymology / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004249:DNA Damage; D004195:Disease Models, Animal; D005090:Exodeoxyribonucleases / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000201:enzymology* / Q000473:pathology; D020022:Genetic Predisposition to Disease; D018859:Hair Follicle / Q000201:enzymology / Q000473:pathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D053484:RecQ Helicases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011038:Rothmund-Thomson Syndrome / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D014162:Transfection; D000071657:Werner Syndrome Helicase
C493956:CDKN1A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D005090:Exodeoxyribonucleases; C097151:Bloom syndrome protein; C506731:RECQL4 protein, human; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase