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

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Nesprin-2-dependent ERK1/2 compartmentalisation regulates the DNA damage response in vascular smooth muscle cell ageing. / Warren, Derek T; Tajsic, T; Porter, L J; Minaisah, R-M; Cobb, A; Jacob, A; Rajgor, D; Zhang, Q P; Shanahan, C M.

In: CELL DEATH AND DIFFERENTIATION, Vol. 22, No. 9, 06.03.2015, p. 1540-50.

Research output: Contribution to journalArticle

Harvard

Warren, DT, Tajsic, T, Porter, LJ, Minaisah, R-M, Cobb, A, Jacob, A, Rajgor, D, Zhang, QP & Shanahan, CM 2015, 'Nesprin-2-dependent ERK1/2 compartmentalisation regulates the DNA damage response in vascular smooth muscle cell ageing.', CELL DEATH AND DIFFERENTIATION, vol. 22, no. 9, pp. 1540-50. https://doi.org/10.1038/cdd.2015.12

APA

Warren, D. T., Tajsic, T., Porter, L. J., Minaisah, R-M., Cobb, A., Jacob, A., ... Shanahan, C. M. (2015). Nesprin-2-dependent ERK1/2 compartmentalisation regulates the DNA damage response in vascular smooth muscle cell ageing. CELL DEATH AND DIFFERENTIATION, 22(9), 1540-50. https://doi.org/10.1038/cdd.2015.12

Vancouver

Warren DT, Tajsic T, Porter LJ, Minaisah R-M, Cobb A, Jacob A et al. Nesprin-2-dependent ERK1/2 compartmentalisation regulates the DNA damage response in vascular smooth muscle cell ageing. CELL DEATH AND DIFFERENTIATION. 2015 Mar 6;22(9):1540-50. https://doi.org/10.1038/cdd.2015.12

Author

Warren, Derek T ; Tajsic, T ; Porter, L J ; Minaisah, R-M ; Cobb, A ; Jacob, A ; Rajgor, D ; Zhang, Q P ; Shanahan, C M. / Nesprin-2-dependent ERK1/2 compartmentalisation regulates the DNA damage response in vascular smooth muscle cell ageing. In: CELL DEATH AND DIFFERENTIATION. 2015 ; Vol. 22, No. 9. pp. 1540-50.

Bibtex Download

@article{572ccfa7159045ada6683794b26f3501,
title = "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.",
author = "Warren, {Derek T} and T Tajsic and Porter, {L J} and R-M Minaisah and A Cobb and A Jacob and D Rajgor and Zhang, {Q P} and Shanahan, {C M}",
year = "2015",
month = "3",
day = "6",
doi = "10.1038/cdd.2015.12",
language = "English",
volume = "22",
pages = "1540--50",
journal = "CELL DEATH AND DIFFERENTIATION",
issn = "1350-9047",
publisher = "Nature Publishing Group",
number = "9",

}

RIS (suitable for import to EndNote) Download

TY - JOUR

T1 - Nesprin-2-dependent ERK1/2 compartmentalisation regulates the DNA damage response in vascular smooth muscle cell ageing.

AU - Warren, Derek T

AU - Tajsic, T

AU - Porter, L J

AU - Minaisah, R-M

AU - Cobb, A

AU - Jacob, A

AU - Rajgor, D

AU - Zhang, Q P

AU - Shanahan, C M

PY - 2015/3/6

Y1 - 2015/3/6

N2 - 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.

AB - 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.

U2 - 10.1038/cdd.2015.12

DO - 10.1038/cdd.2015.12

M3 - Article

VL - 22

SP - 1540

EP - 1550

JO - CELL DEATH AND DIFFERENTIATION

JF - CELL DEATH AND DIFFERENTIATION

SN - 1350-9047

IS - 9

ER -

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