hnRNPA2 Mediated Acetylation Reduces Telomere Length in Response to Mitochondrial Dysfunction

Authors

Manti Guha, University of Pennsylvania
Satish Srinivasan, University of Pennsylvania
F. Bradley Johnson, University of Pennsylvania
Gordon Ruthel, University of Pennsylvania
Kip Guja, Stony Brook University
Miguel Garcia-Diaz, Stony Brook University
Brett A. Kaufman, University of Pittsburg
M. Rebecca Glineburg, Chapman UniversityFollow
JiKang Fang, University of Pennsylvania
Hiroshi Nakagawa, University of Pennsylvania
Jeelan Basha, Jawaharlal Nehru Centre for Advanced Scientific Research
Tapas Kundu, Jawaharlal Nehru Centre for Advanced Scientific Research
Narayan G. Avadhani, University of Pennsylvania

Document Type

Article

Publication Date

11-14-2018

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.

Comments

This article was originally published in PLoS ONE, volume 13, issue 11, in 2018. https://doi.org/10.1371/journal.pone.0206897

Recommended Citation

Manti Guha, Satish Srinivasan, F. Brad Johnson, Gordon Ruthel, Kip Guja, Miguel Garcia-Diaz, Brett A. Kaufman, M. Rebecca Glineburg, J-Kang Fang, Hiroshi Nakagawa, Jeelan Basha, Tapas Kundu, and Narayan Avadhani, “hnRNPA2 mediated acetylation reduces telomere length in response to mitochondrial dysfunction," PLoS ONE, 2018 Nov 14: 13(11). https://doi.org/10.1371/journal.pone.0206897

Copyright

The authors

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.