PARP-1 negatively regulates nucleolar protein pool and mitochondrial activity: a cell protective mechanism.

Abstract

Background: Poly(ADP-ribose) polymerase-1 (PARP-1) is a pan nuclear protein that utilizes NAD⁺ as a substrate for poly(ADP-ribosyl)ation reaction (PARylation), resulting in both auto-modification and the modification of its accepter proteins. Earlier reports suggested that several nucleolar proteins interact and colocalize with PARP-1, leading to their PARylation. However, whether PARP-1 has any role in nucleolar biogenesis and the functional relevance of such a role is still obscure.

Results: Using PARP-1 depleted cells, we investigated the function of PARP-1 in maintaining the nucleolar morphology and protein levels under normal physiological conditions. Our results revealed that several nucleolar proteins like nucleolin, fibrillarin, and nucleophosmin get up-regulated when PARP-1 is depleted. Additionally, in line with the higher accumulation of nucleolin, stably depleted PARP-1 cells show lower activation of caspase-3, lesser annexin-V staining, and reduced accumulation of AIF in the nucleus upon induction of oxidative stress. Concurrently, PARP-1 silenced cells showed higher mitochondrial oxidative phosphorylation and more fragmented and intermediate mitochondria than the parental counterpart, suggesting higher metabolic activity for better survival.

Conclusion: Based on our findings, we demonstrate that PARP-1 may have a role in regulating nucleolar protein levels and mitochondrial activity, thus maintaining the homeostasis between cell protective and cell death pathways, and such cell-protective mechanism could be implicated as the priming state of a pre-cancerous condition or tumour dormancy.