Functional analysis of POLD1 p.ser605del variant: the aging phenotype of MDPL syndrome is associated with an impaired DNA repair capacity

被引：0

作者：

Murdocca, Michela ^{[1
]}

Spitalieri, Paola ^{[1
]}

De Masi, Claudia ^{[1
]}

Udroiu, Ion ^{[2
]}

Marinaccio, Jessica ^{[2
]}

Sanchez, Massimo ^{[3
]}

Talarico, Rosa Valentina ^{[1
]}

Fiorillo, Chiara ^{[4
,5
]}

D'Adamo, Monica ^{[6
]}

Sbraccia, Paolo ^{[6
]}

D'Apice, Maria Rosaria ^{[7
]}

Novelli, Giuseppe ^{[1
,7
]}

Sgura, Antonella ^{[2
]}

Sangiuolo, Federica ^{[1
,7
]}

机构：

[1] Tor Vergata Univ, Dept Biomed & Prevent, I-00133 Rome, Italy

[2] Roma Tre Univ, Dept Sci, I-00154 Rome, Italy

[3] Ist Super Sanita, Dept Cell Biol & Neurosci, I-00161 Rome, Italy

[4] Univ Genoa, Paediat Neurol & Neuromuscular Disorders, I-16147 Genoa, Italy

[5] Ist Giannina Gaslini, I-16147 Genoa, Italy

[6] Tor Vergata Univ, Dept Syst Med, I-00133 Rome, Italy

[7] Tor Vergata Hosp, Lab Med Genet, I-00133 Rome, Italy

来源：

AGING-US | 2021年 / 13卷 / 04期

关键词：

MDPL syndrome; POLD1; gene; age-related disease; DNA repair; telomere damage; POLYMERASE-DELTA; MANDIBULAR HYPOPLASIA; PROGEROID FEATURES; LIPODYSTROPHY; DEAFNESS; REPLICATION; MUTATION; LESSONS; DISEASE; DAMAGE;

D O I：

暂无

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Mandibular hypoplasia, Deafness and Progeroid features with concomitant Lipodystrophy define a rare systemic disorder, named MDPL Syndrome, due to almost always a de novo variant in POLD1 gene, encoding the DNA polymerase delta. We report a MDPL female heterozygote for the recurrent p.Ser605del variant. In order to deepen the functional role of the in frame deletion affecting the polymerase catalytic site of the protein, cellular phenotype has been characterised. MDPL fibroblasts exhibit in vitro nuclear envelope anomalies, accumulation of prelamin A and presence of micronuclei. A decline of cell growth, cellular senescence and a blockage of proliferation in G0/G1 phase complete the aged cellular picture. The evaluation of the genomic instability reveals a delayed recovery from DNA induced-damage. Moreover, the rate of telomere shortening was greater in pathological cells, suggesting the telomere dysfunction as an emerging key feature in MDPL. Our results suggest an alteration in DNA replication/repair function of POLD1 as a primary pathogenetic cause of MDPL. The understanding of the mechanisms linking these cellular characteristics to the accelerated aging and to the wide spectrum of affected tissues and clinical symptoms in the MDPL patients may provide opportunities to develop therapeutic treatments for progeroid syndromes.

引用

页码：4926 / 4945

页数：20