Cellular senescence is a hallmark of normal aging and aging-related syndromes, including the premature aging disorder Hutchinson-Gilford Progeria Syndrome (HGPS), a rare genetic disorder caused by a single mutation in the LMNA gene that results in the constitutive expression of a truncated splicing mutant of lamin A known as progerin. Progerin accumulation leads to increased cellular stresses including unrepaired DNA damage, activation of the p53 signaling pathway and accelerated senescence. We previously established that the p53 isoforms ∆133p53 and p53β regulate senescence in normal human cells. However, their role in premature aging is unknown. Here we report that p53 isoforms are expressed in primary fibroblasts derived from HGPS patients, are associated with their accelerated senescence and that their manipulation can restore the replication capacity of HGPS fibroblasts. We found that in near-senescent HGPS fibroblasts, which exhibit low levels of ∆133p53 and high levels of p53β, restoration of Δ133p53 expression was sufficient to extend replicative lifespan and delay senescence, despite progerin levels and abnormal nuclear morphology remaining unchanged. Conversely, Δ133p53 depletion or p53β overexpression accelerated the onset of senescence in otherwise proliferative HGPS fibroblasts. Our data indicate that Δ133p53 exerts its role by modulating full-length p53 (FLp53) signaling to extend the replicative lifespan and promotes the repair of spontaneous progerin-induced DNA double-strand breaks (DSBs). We showed that Δ133p53 dominant-negative inhibition of FLp53 occurs directly at the p21/CDKN1A and miR-34a promoters, two p53 senescence-associated genes. In addition, Δ133p53 expression increased the expression of DNA repair RAD51, likely through upregulation of E2F1, a transcription factor that activates RAD51, to promote repair of DSBs. In summary, our data indicate that Δ133p53 modulates p53 signaling to repress progerin-induced early onset of senescence in HGPS cells. Therefore, restoration of ∆133p53 expression may be a novel therapeutic strategy to treat aging-associated phenotypes of HGPS in vivo.

中文翻译：

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p53亚型调节人类细胞中的过早衰老。

细胞衰老是正常衰老和与衰老相关的综合症的标志，包括过早衰老症Hutchinson-Gilford早衰综合症（HGPS），这是一种罕见的遗传病，由LMNA基因的单个突变引起，导致截短的组成型表达称为lamerin的lamin A的剪接突变体。早春素的积累导致细胞压力增加，包括未修复的DNA损伤，p53信号通路的激活和衰老加速。我们先前建立了p53亚型∆133p53和p53β调节正常人细胞的衰老。但是，它们在过早衰老中的作用尚不清楚。在这里，我们报道p53亚型在HGPS患者衍生的原代成纤维细胞中表达，它们与加速衰老有关，并且它们的操纵可以恢复HGPS成纤维细胞的复制能力。我们发现，在近衰老的HGPS成纤维细胞中，尽管其早老蛋白水平和异常的核形态保持不变，但其Δ133p53水平低而p53β水平高，恢复Δ133p53的表达足以延长复制寿命并延缓衰老。相反，Δ133p53耗竭或p53β过表达会加速原本增殖的HGPS成纤维细胞的衰老。我们的数据表明，Δ133p53通过调节全长p53（FLp53）信号传导来发挥其作用，以延长复制寿命并促进自发性早衰素诱导的DNA双链断裂（DSBs）的修复。我们表明，FLp53的Δ133p53显性负抑制直接发生在两个p53衰老相关基因p21 / CDKN1A和miR-34a启动子上。此外，Δ133p53的表达可能通过上调激活RAD51的转录因子E2F1的表达上调来促进DNA修复RAD51的表达，从而促进DSB的修复。总而言之，我们的数据表明，Δ133p53调节p53信号传导，从而抑制HGPS细胞中早老素诱导的衰老的早期发作。因此，恢复∆133p53的表达可能是一种在体内治疗与衰老相关的HGPS表型的新颖治疗策略。促进DSB的维修。总而言之，我们的数据表明，Δ133p53调节p53信号传导，从而抑制HGPS细胞中早老素诱导的衰老的早期发作。因此，恢复∆133p53的表达可能是一种在体内治疗与衰老相关的HGPS表型的新颖治疗策略。促进DSB的维修。总而言之，我们的数据表明，Δ133p53调节p53信号传导，从而抑制HGPS细胞中早老素诱导的衰老的早期发作。因此，恢复∆133p53的表达可能是一种在体内治疗与衰老相关的HGPS表型的新颖治疗策略。