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.