Antonella Russo

Chiara Rampazzo

COLETTA, SARA

Elisa Franzolin

Elisa Palumbo

Erika Feltrin

Giorgio Valle

Giovanna Pontarin

Giulia D’Aronco

Loris Bertoldi

Martina Stevanoni

Paola Ferraro

Stefano Cagnin

Vera Bianchi

English

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 nontransformed 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 nontransformed cells

Archivio istituzionale della ricerca - Università di Padova

SAMHD1‐deficient fibroblasts from Aicardi‐Goutières Syndrome patients can escape senescence and accumulate mutations

https://www.research.unipd.it/bitstream/11577/3315986/2/10.1096_fj.201902508R.pdf

SAMHD1‐deficient fibroblasts from Aicardi‐Goutières Syndrome patients can escape senescence and accumulate mutations

SAMHD1‐deficient fibroblasts from Aicardi‐Goutières Syndrome patients can escape senescence and accumulate mutations

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Archivio istituzionale della ricerca - Università di Padova