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

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, resulted in the loss of ATM from DNA lesions. However, ATM signalling and DNA repair remained intact after lamins A/C depletion, whereas nesprin-2 disruption ablated downstream Chk2 activation and induced genomic instability. We conclude that lamins A/C and PML act as scaffolds to organise DNA-repair foci and compartmentalise nesprin-2/ERK signalling. However, nesprin-2/ERK signalling fidelity, but not their compartmentalisation at PML NBs, is essential for efficient DDR in VSMCs.

• Authors: D T Warren, T Tajsic, L J Porter, R M Minaisah, A Cobb, A Jacob, D Rajgor, Q P Zhang, C M Shanahan
• Journal: Cell death and differentiation (Cell Death Differ) Vol. 22 Issue 9 Pg. 1540-50 (Sep 2015) ISSN: 1476-5403 [Electronic] England
• PMID: 25744025 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Lamin Type A
• Microfilament Proteins
• Nerve Tissue Proteins
• Nuclear Proteins
• SYNE2 protein, human
• prelamin A
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3

Topics

• Adult
• Cell Cycle (physiology)
• Cellular Senescence (physiology)
• DNA Damage
• DNA Repair
• Female
• Humans
• Intranuclear Inclusion Bodies (genetics, metabolism)
• Lamin Type A (metabolism)
• Male
• Microfilament Proteins (genetics, metabolism)
• Middle Aged
• Mitogen-Activated Protein Kinase 1 (genetics, metabolism)
• Mitogen-Activated Protein Kinase 3 (genetics, metabolism)
• Muscle, Smooth, Vascular (cytology, enzymology, metabolism)
• Nerve Tissue Proteins (genetics, metabolism)
• Nuclear Proteins (genetics, metabolism)
• Transfection
• Young Adult