TP53 codon 72 polymorphism affects accumulation of mtDNA damage in human cells.
TP53 codon 72 polymorphism affects accumulation of mtDNA damage in human cells.
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DOI：
10.18632/aging.100425
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发表时间：
2012-01
期刊：
影响因子：
--
通讯作者：
Salvioli S
中科院分区：
文献类型：
--
作者：
Altilia S;Santoro A;Malagoli D;Lanzarini C;Ballesteros Álvarez JA;Galazzo G;Porter DC;Crocco P;Rose G;Passarino G;Roninson IB;Franceschi C;Salvioli S
人类TP 53基因的特征是密码子72处的多态性，导致精氨酸至脯氨酸（R/P）取代。两种得到的p53亚型在应激后具有不同的亚细胞定位（分别对于P或R亚型，更多的是核或更多的是线粒体）。p53 P72变体在诱导参与核DNA修复的基因的表达方面比p53 R72更有效。由于p53也参与线粒体DNA（mtDNA）的维持，我们想知道这些p53亚型是否与mtDNA损伤的不同积累有关。我们观察到，与p53 P72细胞相比，p53 R72细胞在鱼藤酮胁迫下积累的mtDNA损伤量较低，并且p53 R72与聚合酶γ的共定位多于p53 P72。我们还分析了425例老年人线粒体DNA D环300 bp片段异质性的体内积累。我们观察到异质性高于5%的受试者在p53 R72/R72组中显著低于预期。总的来说，这些数据表明，TP 53在密码子72的多态性影响mtDNA突变的积累，可能是通过两种p53亚型结合聚合酶γ的能力不同，并可能有助于体内mtDNA突变的积累。
Human TP53 gene is characterised by a polymorphism at codon 72 leading to an Arginine-to-Proline (R/P) substitution. The two resulting p53 isoforms have a different subcellular localisation after stress (more nuclear or more mitochondrial for the P or R isoform, respectively). p53P72 variant is more efficient than p53R72 in inducing the expression of genes involved in nuclear DNA repair. Since p53 is involved also in mitochondrial DNA (mtDNA) maintenance, we wondered whether these p53 isoforms are associated with different accumulation of mtDNA damage. We observed that cells bearing p53R72 accumulate lower amount of mtDNA damage upon rotenone stress with respect to cells bearing p53P72, and that p53R72 co-localises with polymerase gamma more than p53P72. We also analysed the in vivo accumulation of heteroplasmy in a 300 bp fragment of mtDNA D-loop of 425 aged subjects. We observed that subjects with heteroplasmy higher than 5% are significantly less than expected in the p53R72/R72 group. On the whole, these data suggest that the polymorphism of TP53 at codon 72 affects the accumulation of mtDNA mutations, likely through the different ability of the two p53 isoforms to bind to polymerase gamma, and may contribute to in vivo accumulation of mtDNA mutations.
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