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Spartan deficiency causes genomic instability and progeroid phenotypes.

Maskey RS, Kim MS, Baker DJ, Childs B, Malureanu LA, Jeganathan KB, Machida Y, van Deursen JM, Machida YJ - Nat Commun (2014)

Bottom Line: However, the physiological relevance of Spartan has not been established.Cre-mediated depletion of Spartan from conditional knockout mouse embryonic fibroblasts results in impaired lesion bypass, incomplete DNA replication, formation of micronuclei and chromatin bridges and eventually cell death.These data demonstrate that Spartan plays a key role in maintaining structural and numerical chromosome integrity and suggest a link between Spartan insufficiency and progeria.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA.

ABSTRACT
Spartan (also known as DVC1 and C1orf124) is a PCNA-interacting protein implicated in translesion synthesis, a DNA damage tolerance process that allows the DNA replication machinery to replicate past nucleotide lesions. However, the physiological relevance of Spartan has not been established. Here we report that Spartan insufficiency in mice causes chromosomal instability, cellular senescence and early onset of age-related phenotypes. Whereas complete loss of Spartan causes early embryonic lethality, hypomorphic mice with low amounts of Spartan are viable. These mice are growth retarded and develop cataracts, lordokyphosis and cachexia at a young age. Cre-mediated depletion of Spartan from conditional knockout mouse embryonic fibroblasts results in impaired lesion bypass, incomplete DNA replication, formation of micronuclei and chromatin bridges and eventually cell death. These data demonstrate that Spartan plays a key role in maintaining structural and numerical chromosome integrity and suggest a link between Spartan insufficiency and progeria.

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Premature ageing phenotypes in SprtnH/H mice.(a) Representative images of 12-month-old Sprtn+/+ and SprtnH/H female mice. Note lordokyphosis in SprtnH/H indicated by the dotted red line. Scale bar, 1 cm. (b) Representative images of the eyes of Sprtn+/+ and SprtnH/H female mice. Note a cataract in SprtnH/H. (c) Body weight, fat mass, body fat percentage and adipose depot weights of 12-month-old Sprtn+/+ and SprtnH/H female mice (n=5, mean±s.d.). Values are normalized to the average of the Sprtn+/+ mice. Because of the smaller body size of the SprtnH/H mice, adipose depot measurements were first calculated relative to body weight. (d) Fat cell diameter measurements (n=5, mean±s.d.). (e) IAT of 12-month-old mice stained for SA-β-gal activity. (f) Relative expression of senescence markers in 12-month-old IAT (n=5, mean±s.d.). Values were normalized to Gapdh and are relative to Sprtn+/+ IAT. (g) Treadmill exercise ability of 12-month-old Sprtn+/+ and SprtnH/H female mice. Exercise time, distance travelled and workload performed are shown (n=5, mean±s.d.). For all panels, statistical significance is as follows: *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 (two-tailed unpaired t-test).
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f7: Premature ageing phenotypes in SprtnH/H mice.(a) Representative images of 12-month-old Sprtn+/+ and SprtnH/H female mice. Note lordokyphosis in SprtnH/H indicated by the dotted red line. Scale bar, 1 cm. (b) Representative images of the eyes of Sprtn+/+ and SprtnH/H female mice. Note a cataract in SprtnH/H. (c) Body weight, fat mass, body fat percentage and adipose depot weights of 12-month-old Sprtn+/+ and SprtnH/H female mice (n=5, mean±s.d.). Values are normalized to the average of the Sprtn+/+ mice. Because of the smaller body size of the SprtnH/H mice, adipose depot measurements were first calculated relative to body weight. (d) Fat cell diameter measurements (n=5, mean±s.d.). (e) IAT of 12-month-old mice stained for SA-β-gal activity. (f) Relative expression of senescence markers in 12-month-old IAT (n=5, mean±s.d.). Values were normalized to Gapdh and are relative to Sprtn+/+ IAT. (g) Treadmill exercise ability of 12-month-old Sprtn+/+ and SprtnH/H female mice. Exercise time, distance travelled and workload performed are shown (n=5, mean±s.d.). For all panels, statistical significance is as follows: *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 (two-tailed unpaired t-test).

Mentions: As young adults, SprtnH/H mice exhibited no overt phenotypes other than dwarfism. However, by 12 months of age, all SprtnH/H mice (seven out of seven mice) had developed lordokyphosis (concavity in the curvature of the lumbar and cervical spine), cataracts and cachexia (Fig. 7a,b), three phenotypes often seen in mouse models of progeria232425. The total fat mass and percentage of body fat of these mice were dramatically reduced (Fig. 7c). In-depth analysis of individual fat depots revealed that the relative weights of the paraovarian, inguinal adipose tissue (IAT), perirenal and subscapular adipose tissue were all significantly reduced in size (Fig. 7c). Consistent with fat tissue atrophy, fat cells in SprtnH/H IAT were significantly smaller in size (Fig. 7d). Furthermore, IAT stained highly positive for senescence-associated-β-galactosidase (SA-β-GAL) and showed increased levels of key senescence markers, including p16Ink4a, p19Arf and PAI-1 (Fig. 7e,f). These data suggest that increased accumulation of cellular senescence in fat causes dysfunction and atrophy of this tissue. Lordokyphosis in progeroid mouse models is often associated with osteoporosis and/or muscle wasting2426. However, neither disorder seemed to apply to SprtnH/H mice as their bone mineral content and density (Supplementary Fig. 6a,b) and gastrocnemius, abdominal and paraspinal muscle fibre diameters (Supplementary Fig. 6c–e) were normal. Consistent with segmental progeria, SprtnH/H mice showed impaired exercise ability as measured by the use of a treadmill: the duration of exercise, the distance travelled and the overall amount of work performed were all reduced at the age of 12 months (Fig. 7g). Taken together, these data suggest that the reduced expression of Sprtn leads to development of various progeroid phenotypes, including dwarfism, cataracts, lordokyphosis, fat tissue dysfunction and accumulation of senescent cells.


Spartan deficiency causes genomic instability and progeroid phenotypes.

Maskey RS, Kim MS, Baker DJ, Childs B, Malureanu LA, Jeganathan KB, Machida Y, van Deursen JM, Machida YJ - Nat Commun (2014)

Premature ageing phenotypes in SprtnH/H mice.(a) Representative images of 12-month-old Sprtn+/+ and SprtnH/H female mice. Note lordokyphosis in SprtnH/H indicated by the dotted red line. Scale bar, 1 cm. (b) Representative images of the eyes of Sprtn+/+ and SprtnH/H female mice. Note a cataract in SprtnH/H. (c) Body weight, fat mass, body fat percentage and adipose depot weights of 12-month-old Sprtn+/+ and SprtnH/H female mice (n=5, mean±s.d.). Values are normalized to the average of the Sprtn+/+ mice. Because of the smaller body size of the SprtnH/H mice, adipose depot measurements were first calculated relative to body weight. (d) Fat cell diameter measurements (n=5, mean±s.d.). (e) IAT of 12-month-old mice stained for SA-β-gal activity. (f) Relative expression of senescence markers in 12-month-old IAT (n=5, mean±s.d.). Values were normalized to Gapdh and are relative to Sprtn+/+ IAT. (g) Treadmill exercise ability of 12-month-old Sprtn+/+ and SprtnH/H female mice. Exercise time, distance travelled and workload performed are shown (n=5, mean±s.d.). For all panels, statistical significance is as follows: *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 (two-tailed unpaired t-test).
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Related In: Results  -  Collection

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Show All Figures
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f7: Premature ageing phenotypes in SprtnH/H mice.(a) Representative images of 12-month-old Sprtn+/+ and SprtnH/H female mice. Note lordokyphosis in SprtnH/H indicated by the dotted red line. Scale bar, 1 cm. (b) Representative images of the eyes of Sprtn+/+ and SprtnH/H female mice. Note a cataract in SprtnH/H. (c) Body weight, fat mass, body fat percentage and adipose depot weights of 12-month-old Sprtn+/+ and SprtnH/H female mice (n=5, mean±s.d.). Values are normalized to the average of the Sprtn+/+ mice. Because of the smaller body size of the SprtnH/H mice, adipose depot measurements were first calculated relative to body weight. (d) Fat cell diameter measurements (n=5, mean±s.d.). (e) IAT of 12-month-old mice stained for SA-β-gal activity. (f) Relative expression of senescence markers in 12-month-old IAT (n=5, mean±s.d.). Values were normalized to Gapdh and are relative to Sprtn+/+ IAT. (g) Treadmill exercise ability of 12-month-old Sprtn+/+ and SprtnH/H female mice. Exercise time, distance travelled and workload performed are shown (n=5, mean±s.d.). For all panels, statistical significance is as follows: *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 (two-tailed unpaired t-test).
Mentions: As young adults, SprtnH/H mice exhibited no overt phenotypes other than dwarfism. However, by 12 months of age, all SprtnH/H mice (seven out of seven mice) had developed lordokyphosis (concavity in the curvature of the lumbar and cervical spine), cataracts and cachexia (Fig. 7a,b), three phenotypes often seen in mouse models of progeria232425. The total fat mass and percentage of body fat of these mice were dramatically reduced (Fig. 7c). In-depth analysis of individual fat depots revealed that the relative weights of the paraovarian, inguinal adipose tissue (IAT), perirenal and subscapular adipose tissue were all significantly reduced in size (Fig. 7c). Consistent with fat tissue atrophy, fat cells in SprtnH/H IAT were significantly smaller in size (Fig. 7d). Furthermore, IAT stained highly positive for senescence-associated-β-galactosidase (SA-β-GAL) and showed increased levels of key senescence markers, including p16Ink4a, p19Arf and PAI-1 (Fig. 7e,f). These data suggest that increased accumulation of cellular senescence in fat causes dysfunction and atrophy of this tissue. Lordokyphosis in progeroid mouse models is often associated with osteoporosis and/or muscle wasting2426. However, neither disorder seemed to apply to SprtnH/H mice as their bone mineral content and density (Supplementary Fig. 6a,b) and gastrocnemius, abdominal and paraspinal muscle fibre diameters (Supplementary Fig. 6c–e) were normal. Consistent with segmental progeria, SprtnH/H mice showed impaired exercise ability as measured by the use of a treadmill: the duration of exercise, the distance travelled and the overall amount of work performed were all reduced at the age of 12 months (Fig. 7g). Taken together, these data suggest that the reduced expression of Sprtn leads to development of various progeroid phenotypes, including dwarfism, cataracts, lordokyphosis, fat tissue dysfunction and accumulation of senescent cells.

Bottom Line: However, the physiological relevance of Spartan has not been established.Cre-mediated depletion of Spartan from conditional knockout mouse embryonic fibroblasts results in impaired lesion bypass, incomplete DNA replication, formation of micronuclei and chromatin bridges and eventually cell death.These data demonstrate that Spartan plays a key role in maintaining structural and numerical chromosome integrity and suggest a link between Spartan insufficiency and progeria.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA.

ABSTRACT
Spartan (also known as DVC1 and C1orf124) is a PCNA-interacting protein implicated in translesion synthesis, a DNA damage tolerance process that allows the DNA replication machinery to replicate past nucleotide lesions. However, the physiological relevance of Spartan has not been established. Here we report that Spartan insufficiency in mice causes chromosomal instability, cellular senescence and early onset of age-related phenotypes. Whereas complete loss of Spartan causes early embryonic lethality, hypomorphic mice with low amounts of Spartan are viable. These mice are growth retarded and develop cataracts, lordokyphosis and cachexia at a young age. Cre-mediated depletion of Spartan from conditional knockout mouse embryonic fibroblasts results in impaired lesion bypass, incomplete DNA replication, formation of micronuclei and chromatin bridges and eventually cell death. These data demonstrate that Spartan plays a key role in maintaining structural and numerical chromosome integrity and suggest a link between Spartan insufficiency and progeria.

Show MeSH
Related in: MedlinePlus