NUPR1 protects against hyperPARylation-dependent cell death

Abstract

Proteomic, cellular and biochemical analysis of the stress protein NUPR1 reveals that it binds to PARP1 into the nucleus and inhibits PARP1 activity in vitro. Mutations on residues Ala33 or Thr68 of NUPR1 or treatment with its inhibitor ZZW-115 inhibits this effect. PARylation induced by 5-fluorouracil (5-FU) treatment is strongly enhanced by ZZW-115 and associated with a decrease of NAD+/NADH ratio and rescued by the PARP inhibitor olaparib. Cell death induced by ZZW-115 treatment of pancreas cancer-derived cells is rescued by olaparib and improved with PARG inhibitor PDD00017273. The mitochondrial catastrophe induced by ZZW-115 treatment or by genetic inactivation of NUPR1 is associated to a hyperPARylation of the mitochondria, disorganization of the mitochondrial network, mitochondrial membrane potential decrease, and with increase of superoxide production, intracellular level of reactive oxygen species (ROS) and cytosolic levels of Ca2+. These features are rescued by olaparib or NAD+ precursor nicotinamide mononucleotide in a dose-dependent manner and partially by antioxidants treatments. In conclusion, inactivation of NUPR1 induces a hyperPARylation, which in turn, induces a mitochondrial catastrophe and consequently a cell death through a non-canonical Parthanatos, since apoptosis inducing-factor (AIF) is not translocated out of the mitochondria.

Human PARP1 substrates and regulators of its catalytic activity: An updated overview

“…NUPR1 is a nuclear stress protein which is able to bind to PARP1 and inhibit its enzymatic activity. Pharmacological inhibition of NUPR1 causes deleterious PARylation, mitochondrial dysfunction and cell death (Santofimia-Castano et al, 2022). Han et al found that SNORA73, a chromatin-associated small nucleolar RNAs, restrains PARP1 auto-PARylation and contributes to genome instability in hematopoietic malignancy (Han et al, 2022).…”

Poly(ADP-ribose) polymerase-1 and its ambiguous role in cellular life and death

“…Parthanatos has also been involved in human psoriasis in which PARP1 is overactivated downstream of the NAD + generating enzyme nicotinamide phosphoribosyltransferase (NAMPT) and the translocation of AIF from mitochondria to nuclei can be observed in skin lesions [ 26 ]. As an aside, cancer cells can die in response to specific drugs or drug combinations in a PARP1-dependent fashion [ 27 – 29 ]. Altogether, it appears that, outside of the realm of oncology, PARP1 inhibition might be useful for the treatment of diseases, many of which are caused by the acute, massive or chronic, insidious loss of neurons.…”