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PLoS One. 2018 Nov 14;13(11):e0206897. doi: 10.1371/journal.pone.0206897. eCollection 2018.

hnRNPA2 mediated acetylation reduces telomere length in response to mitochondrial dysfunction.

Author information

1
Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States of America.
2
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America.
3
Penn Vet Imaging Core, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States of America.
4
Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY, United States of America.
5
Vascular Medicine Institute, University of Pittsburg, Pittsburgh, PA United States of America.
6
Department of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America.
7
Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore, India.

Abstract

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.

Conflict of interest statement

The authors have declared that no competing interests exist.

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