Nesprin-2-dependent ERK1/2 compartmentalisation regulates the DNA damage response in vascular smooth muscle cell ageing

Cell Death and Differentiation
Derek T WarrenCatherine M Shanahan

Abstract

Prelamin A accumulation and persistent DNA damage response (DDR) are hallmarks of vascular smooth muscle cell (VSMC) ageing and dysfunction. Although prelamin A is proposed to interfere with DNA repair, our understanding of the crosstalk between prelamin A and the repair process remains limited. The extracellular signal-regulated kinases 1 and 2 (ERK1/2) have emerged as key players in the DDR and are known to enhance ataxia telangiectasia-mutated protein (ATM) activity at DNA lesions, and in this study, we identified a novel relationship between prelamin A accumulation and ERK1/2 nuclear compartmentalisation during VSMC ageing. We show both prelamin A accumulation and increased DNA damage occur concomitantly, before VSMC replicative senescence, and induce the localisation of ERK1/2 to promyelocytic leukaemia protein nuclear bodies (PML NBs) at the sites of DNA damage via nesprin-2 and lamin A interactions. Importantly, VSMCs treated with DNA damaging agents also displayed prelamin A accumulation and ERK compartmentalisation at PML NBs, suggesting that prelamin A and nesprin-2 are novel components of the DDR. In support of this, disruption of ERK compartmentalisation at PML NBs, by either depletion of nesprin-2 or lamins A/C, re...Continue Reading

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Citations

Mar 28, 2017·Journal of Internal Medicine·M TesauroN Di Daniele
Jan 14, 2017·Current Opinion in Cell Biology·Beatriz Dorado, Vicente Andrés
Jan 10, 2018·Frontiers in Cardiovascular Medicine·Leah A Pagnozzi, Jonathan T Butcher
May 30, 2019·Cold Spring Harbor Perspectives in Biology·Diane Proudfoot
Oct 5, 2019·Experimental Biology and Medicine·Muriel W Lambert
May 15, 2020·Arteriosclerosis, Thrombosis, and Vascular Biology·Melinda DuerCatherine M Shanahan
May 10, 2016·Nucleus·Agnieszka DobrzynskaPeter Askjaer
Jan 17, 2019·Cell Death and Differentiation·Margarita-Elena Papandreou, Nektarios Tavernarakis
May 23, 2018·Biochemical Society Transactions·Can ZhouQiuping Zhang
Aug 14, 2019·Journal of Biological Engineering·Tasneem BouzidJung Yul Lim
May 25, 2020·Ageing Research Reviews·Vittoria CenniGiovanna Lattanzi

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Methods Mentioned

BETA
flow cytometry
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Volocity

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