TY - JOUR
T1 - Telomere Dysfunction Induces Sirtuin Repression that Drives Telomere-Dependent Disease
AU - Amano, Hisayuki
AU - Chaudhury, Arindam
AU - Rodriguez-Aguayo, Cristian
AU - Lu, Lan
AU - Akhanov, Viktor
AU - Catic, Andre
AU - Popov, Yury V.
AU - Verdin, Eric
AU - Johnson, Hannah
AU - Stossi, Fabio
AU - Sinclair, David A.
AU - Nakamaru-Ogiso, Eiko
AU - Lopez-Berestein, Gabriel
AU - Chang, Jeffrey T.
AU - Neilson, Joel R.
AU - Meeker, Alan
AU - Finegold, Milton
AU - Baur, Joseph A.
AU - Sahin, Ergun
N1 - Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/6/4
Y1 - 2019/6/4
N2 - Telomere shortening is associated with stem cell decline, fibrotic disorders, and premature aging through mechanisms that are incompletely understood. Here, we show that telomere shortening in livers of telomerase knockout mice leads to a p53-dependent repression of all seven sirtuins. P53 regulates non-mitochondrial sirtuins (Sirt1, 2, 6, and 7) post-transcriptionally through microRNAs (miR-34a, 26a, and 145), while the mitochondrial sirtuins (Sirt3, 4, and 5) are regulated in a peroxisome proliferator-activated receptor gamma co-activator 1 alpha-/beta-dependent manner at the transcriptional level. Administration of the NAD(+) precursor nicotinamide mononucleotide maintains telomere length, dampens the DNA damage response and p53, improves mitochondrial function, and, functionally, rescues liver fibrosis in a partially Sirt1-dependent manner. These studies establish sirtuins as downstream targets of dysfunctional telomeres and suggest that increasing Sirt1 activity alone or in combination with other sirtuins stabilizes telomeres and mitigates telomere-dependent disorders. Telomere dysfunction is implicated in the promotion of tissue damage and fibrosis through mechanisms that are incompletely understood. Amano et al. show that telomere dysfunction in liver tissue downregulates sirtuins through p53-dependent mechanisms. Increasing NAD(+) stabilizes telomeres, dampens DNA damage response, and improves telomere-dependent fibrosis in a partially Sirt1-dependent manner.
AB - Telomere shortening is associated with stem cell decline, fibrotic disorders, and premature aging through mechanisms that are incompletely understood. Here, we show that telomere shortening in livers of telomerase knockout mice leads to a p53-dependent repression of all seven sirtuins. P53 regulates non-mitochondrial sirtuins (Sirt1, 2, 6, and 7) post-transcriptionally through microRNAs (miR-34a, 26a, and 145), while the mitochondrial sirtuins (Sirt3, 4, and 5) are regulated in a peroxisome proliferator-activated receptor gamma co-activator 1 alpha-/beta-dependent manner at the transcriptional level. Administration of the NAD(+) precursor nicotinamide mononucleotide maintains telomere length, dampens the DNA damage response and p53, improves mitochondrial function, and, functionally, rescues liver fibrosis in a partially Sirt1-dependent manner. These studies establish sirtuins as downstream targets of dysfunctional telomeres and suggest that increasing Sirt1 activity alone or in combination with other sirtuins stabilizes telomeres and mitigates telomere-dependent disorders. Telomere dysfunction is implicated in the promotion of tissue damage and fibrosis through mechanisms that are incompletely understood. Amano et al. show that telomere dysfunction in liver tissue downregulates sirtuins through p53-dependent mechanisms. Increasing NAD(+) stabilizes telomeres, dampens DNA damage response, and improves telomere-dependent fibrosis in a partially Sirt1-dependent manner.
KW - liver disease
KW - metabolism
KW - p53
KW - sirtuins
KW - telomeres
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U2 - 10.1016/j.cmet.2019.03.001
DO - 10.1016/j.cmet.2019.03.001
M3 - Article
C2 - 30930169
AN - SCOPUS:85066236523
SN - 1550-4131
VL - 29
SP - 1274-1290.e9
JO - Cell Metabolism
JF - Cell Metabolism
IS - 6
ER -