Back to Search
Start Over
SAMHD1-deficient fibroblasts from Aicardi-Goutières Syndrome patients can escape senescence and accumulate mutations.
- Source :
-
FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2020 Jan; Vol. 34 (1), pp. 631-647. Date of Electronic Publication: 2019 Nov 26. - Publication Year :
- 2020
-
Abstract
- In mammalian cells, the catabolic activity of the dNTP triphosphohydrolase SAMHD1 sets the balance and concentration of the four dNTPs. Deficiency of SAMHD1 leads to unequally increased pools and marked dNTP imbalance. Imbalanced dNTP pools increase mutation frequency in cancer cells, but it is not known if the SAMHD1-induced dNTP imbalance favors accumulation of somatic mutations in non-transformed cells. Here, we have investigated how fibroblasts from Aicardi-Goutières Syndrome (AGS) patients with mutated SAMHD1 react to the constitutive pool imbalance characterized by a huge dGTP pool. We focused on the effects on dNTP pools, cell cycle progression, dynamics and fidelity of DNA replication, and efficiency of UV-induced DNA repair. AGS fibroblasts entered senescence prematurely or upregulated genes involved in G1/S transition and DNA replication. The normally growing AGS cells exhibited unchanged DNA replication dynamics and, when quiescent, faster rate of excision repair of UV-induced DNA damages. To investigate whether the lack of SAMHD1 affects DNA replication fidelity, we compared de novo mutations in AGS and WT cells by exome next-generation sequencing. Somatic variant analysis indicated a mutator phenotype suggesting that SAMHD1 is a caretaker gene whose deficiency is per se mutagenic, promoting genome instability in non-transformed cells.<br /> (© 2019 Federation of American Societies for Experimental Biology.)
- Subjects :
- DNA Damage genetics
DNA Replication genetics
Humans
Monomeric GTP-Binding Proteins metabolism
SAM Domain and HD Domain-Containing Protein 1 genetics
Autoimmune Diseases of the Nervous System genetics
Fibroblasts metabolism
Mutation genetics
Nervous System Malformations genetics
SAM Domain and HD Domain-Containing Protein 1 deficiency
Subjects
Details
- Language :
- English
- ISSN :
- 1530-6860
- Volume :
- 34
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- FASEB journal : official publication of the Federation of American Societies for Experimental Biology
- Publication Type :
- Academic Journal
- Accession number :
- 31914608
- Full Text :
- https://doi.org/10.1096/fj.201902508R