How do I kill thee? Let me count the ways: p53 regulates PARP-1 dependent necrosis

Abstract

Understanding the impact of the p53 tumor suppressor pathway on the regulation of genome integrity, cancer development, and cancer treatment has intrigued scientists and clinicians for decades. It appears that the p53 pathway is a central node for nearly all cell stress responses, including: gene expression, DNA repair, cell cycle arrest, metabolic adjustments, apoptosis, and senescence. In the past decade, it has become increasingly clear that p53 function is directly regulated by poly(ADP-ribose) polymerase-1 (PARP-1), a nuclear enzyme involved in DNA repair signaling. Here, we will discuss the impact of PARP-1 on p53 function, along with a recently described novel role for the reciprocal regulation of p53 regulated, PARP-1 dependent necrosis following DNA damage.

Keywords: PARP-1; ROS; apoptosis; necrosis; p53.

Figure 1

p53 activation engages multiple cell death pathways. In response to cellular stress such as DNA damage, oncogene activation, or hypoxia, the p53 tumor suppressor is activated and stabilized. Active p53 is able to interact with various cellular signaling pathways. Depending on the cellular context, p53 activation can lead to at least three distinct cell death phenotypes: autophagy, apoptosis, or necrosis.

Figure 2

DNA damage induced PARP-1 activation and phenotypes. Following DNA damage, PARP-1 is recruited to the sites of DNA lesions. Depending on the level of stress, PARP-1 activation results in cellular survival or necrosis. Following a mild stress, components of DNA repair machinery such as XRCC1 and DNA-PK are ADP-ribosylated and recruited to the sites of damage, thus promoting cell survival. In response to severe DNA damage, PARP-1 activation and the production of poly(ADP-ribose) polymers greatly increases leading to the consumption of NAD⁺ reserves and necrosis.

Figure 3

Functional relationships between the PARP-1 and p53 pathways. Upon cellular stress, PARP-1 is known to have several effects on p53, including the stabilization and poly(ADP-ribosyl)ation of p53 which regulates its transcriptional activity. In addition, cellular stress can also activate p53, which induces PARP-1 function. The mechanism of p53-induced PARP-1 activation remains unknown, but likely includes a combination of transcriptional and posttranslational events. See text for further information.