in this way, JNK activity regulates several important cellular functions including cell growth, differentiation, survival and apoptosis. JNK1 is involved in apoptosis, neurodegeneration, cell differentiation and proliferation, inflammatory conditions and cytokine production mediated by AP-1 (activation protein 1) such as RANTES, IL-8 and GM-CSF. Recently, JNK1 has been found to regulate Jun protein turnover by phosphorylation and activation of the ubiquitin ligase Itch. Neurotrophin binding to p75NTR activates a JNK signaling pathway causing apoptosis of developing neurons. JNK, through a series of intermediates, activates p53 and p53 activates Bax which initiates apoptosis. TrkA can prevent p75NTR-mediated JNK pathway apoptosis. JNK can directly phosphorylate Bim-EL, a splicing isoform of Bcl-2 interacting mediator of cell death (Bim), which activates Bim-EL apoptotic activity. JNK activation is required for apoptosis but c-jun, a protein involved in the JNK pathway, is not always required. Roles in DNA repair The packaging of eukaryotic DNA into chromatin presents a barrier to all DNA-based processes that require recruitment of enzymes to their sites of action. To allow repair of double-strand breaks in DNA, the chromatin must be remodeled. Chromatin relaxation occurs rapidly at the site of a DNA damage. In one of the earliest steps, JNK phosphorylates SIRT6 on serine 10 in response to double-strand breaks (DSBs) or other DNA damage, and this step is required for efficient repair of DSBs. Phosphorylation of SIRT6 on S10 facilitates the mobilization of SIRT6 to DNA damage sites, where SIRT6 then recruits and mono-phosphorylates poly (ADP-ribose) polymerase 1 (PARP1) at DNA break sites. Half maximum accumulation of PARP1 occurs within 1.6 seconds after the damage occurs. The chromatin remodeler Alc1 quickly attaches to the product of PARP1 action, a poly-ADP ribose chain, allowing half of the maximum chromatin relaxation, presumably due to action of Alc1, by 10 seconds. This allows recruitment of the DNA repair enzyme MRE11, to initiate DNA repair, within 13 seconds. Removal of UV-induced DNA photoproducts, during transcription coupled nucleotide excision repair (TC-NER), depends on JNK phosphorylation of DGCR8 on serine 153. While DGCR8 is usually known to function in microRNA biogenesis, the microRNA-generating activity of DGCR8 is not required for DGCR8-dependent removal of UV-induced photoproducts. Nucleotide excision repair is also needed for repair of oxidative DNA damage due to hydrogen peroxide (), and DGCR8 depleted cells are sensitive to . In aging In Drosophila, flies with mutations that augment JNK signaling accumulate less oxidative damage and live