hnRNPA2 mediated acetylation reduces telomere length in response to mitochondrial dysfunction

Telomeres protect against chromosomal damage. Accelerated telomere loss has been associated with premature aging syndromes such as Werner’s syndrome and Dyskeratosis Congenita, while, progressive telomere loss activates a DNA damage response leading to chromosomal instability, typically observed in cancer cells and senescent cells. Therefore, identifying mechanisms of telomere length maintenance is critical for understanding human pathologies. In this paper we demonstrate that mitochondrial dysfunction plays a causal role in telomere shortening. Furthermore, hnRNPA2, a mitochondrial stress responsive lysine acetyltransferase (KAT) acetylates telomere histone H4at lysine 8 of (H4K8) and this acetylation is associated with telomere attrition. Cells containing dysfunctional mitochondria have higher telomere H4K8 acetylation and shorter telomeres independent of cell proliferation rates. Ectopic expression of KAT mutant hnRNPA2 rescued telomere length possibly due to impaired H4K8 acetylation coupled with inability to activate telomerase expression. The phenotypic outcome of telomere shortening in immortalized cells included chromosomal instability (end-fusions) and telomerase activation, typical of an oncogenic transformation; while in non-telomerase expressing fibroblasts, mitochondrial dysfunction induced-telomere attrition resulted in senescence. Our findings provide a mechanistic association between dysfunctional mitochondria and telomere loss and therefore describe a novel epigenetic signal for telomere length maintenance.端粒（Telomeres）可抵御染色体损伤。端粒加速丢失与沃纳综合征（Werner’s syndrome）、先天性角化不良（Dyskeratosis Congenita）等早衰综合征密切相关；而进行性端粒丢失会激活DNA损伤应答（DNA damage response），引发染色体不稳定性，该现象常见于癌细胞与衰老细胞中。因此，阐明端粒长度维持的分子机制，对解析人类疾病的病理过程至关重要。 本研究证实，线粒体功能障碍（mitochondrial dysfunction）在端粒缩短过程中发挥因果性作用。进一步研究发现，异质性细胞核核糖蛋白A2（hnRNPA2）作为线粒体应激响应性赖氨酸乙酰转移酶（KAT），可在第8位赖氨酸位点（H4K8）乙酰化端粒组蛋白H4，且该乙酰化修饰与端粒耗竭相关。携带功能异常线粒体的细胞，其端粒H4K8乙酰化水平更高、端粒长度更短，且该效应不依赖于细胞增殖速率。异位表达赖氨酸乙酰转移酶突变型hnRNPA2可挽救端粒长度，这可能源于该突变体导致的H4K8乙酰化受损，以及无法激活端粒酶的表达。 在永生化细胞中，端粒缩短的表型效应包括染色体不稳定性（染色体末端融合）与端粒酶激活，这是致癌转化的典型特征；而在不表达端粒酶的成纤维细胞中，线粒体功能障碍诱导的端粒耗竭会引发细胞衰老。本研究结果揭示了功能异常线粒体与端粒丢失之间的机制性关联，从而为端粒长度维持提供了一种新型表观遗传信号。