Role of PARP Cleavage in Apoptosis

Today I begin to talk about some relationships between PARP and apoptosis. Apoptosis plays important roles in development, immunological competence, and homeostasis. It is characterized by marked changes in cellular morphology, including chromatin condensation, membrane blebbing, and cleavage of poly(ADP-ribose) polymerase (PARP).

Cleavage of poly-(ADP-ribose) polymerase is a process occurring early during the execution phase of apoptosis. PARP is cleaved by caspase-3 early during apoptosis in many different cell lines. The cleavage of PARP between Asp214 and Gly215 results in the separation of the two zinc-finger DNA-binding motifs in the NH2-terminal region of the enzyme from the automodification and catalytic domains. Although in many experimental systems PARP cleavage indicates a point of no return, the significance of this proteolytic step for apoptosis remains unclear. By comparing the susceptibility of cells from wild-type mice and PARP?/? mice to several inducers of apoptosis, a conclusion could be got that neither activation nor cleavage of PARP has a causal role in apoptotic cell death of primary, non-transformed cells. And in the apoptosis and the early stages of differentiation-linked DNA replication, a transient burst of PAR synthesis and PARP expression occurs early, prior to internucleosomal DNA cleavage before commitment to apoptosis as well as at the round of DNA replication prior to the onset of terminal differentiation.

In intact human osteosarcoma cells undergoing spontaneous apoptosis, both PARP and PAR decreased after this early peak, concomitant with the inactivation and cleavage of PARP by caspase-3 and the onset of substantial DNA and nuclear fragmentation. Many data suggest that PARP may play a role in the expression of these proteins, perhaps by interacting with a site in the promoters for these genes.

Allergic asthma and chronic obstructive pulmonary disease (COPD) are complex respiratory disorders. Chronic obstructive pulmonary disease, also known as chronic obstructive airway disease, could lead to a narrowed airways, a limitation of the flow of air to and from the lungs, causing shortness of breath. This disease is commonly caused by tobacco smoking. Oxidative injury and an abnormal inflammatory response in the lung are key factors in the pathogenesis of both asthma and chronic obstructive pulmonary disease. In these disorders nuclear factor–kB (NF-kB) is induced by oxidative stress and reactive oxygen species(ROS) is released by inflammatory cells in the airways. While the IL8, TNF, RANTES are expressed, the inflammatory cell infiltration is triggered.

In vitro and in vivo it has been demonstrated ROS are inducers of DNA damage and breakage. The resulting DNA strand breaks could induce the PARP-1 to bind it. Then the complex of PARP-1, long branched chains of poly(ADP-ribose) (PAR), with nicotinamide adenine cleotide (NAD) is formed and takes part in recognizing of DNA damage, DNA repair and apoptosis. But in the condition of massive DNA damage, excessive activation of PARP-1 overly consumes the cellular pools of NAD and ATP. Cell would die for this reason. This phenomenon has been observed in vascular collapse in shock, streptozotocin-induced diabetes, gluta mate neurotoxicity and so on.

Pharmacologic inhibition of PARP-1 by PARP inhibitor offers a novel idea to the treatment of such conditions. Some PARP inhibitor could reduce markedly the extent of brain damage and provide protection against chronic colitis.Many scientists believe that PARP plays an important role in inflammation.

Numerologist Warda is hooked on OG-L002 fishing, collecting. And lastly her encouragement comes from socializing along with her companions.