NEDD8

NEDD8 is a

There are several different proteases which can remove NEDD8 from protein conjugates. UCHL1, UCHL3 and USP21 proteases have dual specificity for NEDD8 and ubiquitin. Proteases specific for NEDD8 removal are the COP9 signalosome which removes NEDD8 from the CUL1 subunit of SCF ubiquitin ligases, and NEDP1 (or DEN1, SENP8).[10]

Role in DNA repair

As shown by Brown et al.,^[8] NEDD8 accumulation at DNA-damage sites is a highly dynamic process. Neddylation is needed during a short period of the global genome repair (GGR) sub-pathway of DNA nucleotide excision repair (NER). In GGR of NER, after DNA damage is caused by UV irradiation, Cul4A in the DNA damage binding protein 2 (DDB2) complex is activated by NEDD8, and this allows GGR-NER to proceed to remove the damage.^[11]

Neddylation also has a role in repair of double-strand breaks.^[8] Non-homologous end joining(NHEJ) is a DNA repair pathway frequently used to repair DNA double-strand breaks. The first step in this pathway depends on the Ku70/Ku80 heterodimer that forms a highly stable ring structure encircling DNA ends.^[12] But the Ku heterodimer needs to be removed when NHEJ is completed, or it blocks transcription or replication. The Ku heterodimer is ubiquitylated in a DNA-damage and neddylation-dependent manner to promote the release of Ku and other NHEJ factors from the site of repair after the process is completed.^[8]

In cancer chemotherapy

As discussed by Jin and Roberston in their review,^[13] silencing of a DNA repair gene by hypermethylation of its promoter may be a very early step in progression to cancer. Gene silencing of a DNA repair gene at the transcription level is proposed to act similarly to a germ-line mutation in a DNA repair gene. Loss of DNA repair capability by either mechanism introduces genome instability and predisposes the cell and its descendants to progression to cancer. Epigenetically silenced DNA repair genes occur frequently in the 17 most common cancers (see e.g. Frequency of hypermethylation of DNA repair genes in cancer).^[13]

As discussed above, activated-NEDD8 is needed in two DNA repair pathways: NER and NHEJ. If activation of NEDD8 is inhibited, cells with induced deficiency of NER or NHEJ may then die because of deficient DNA repair leading to accumulation of DNA damages. The effect of NEDD8 inhibition may be greater for cancer cells than for normal cells if the cancer cells are independently deficient in DNA repair due to prior epigenetic silencing of DNA repair genes active in alternative pathways (see synthetic lethality).

Pevonedistat (MLN4924), a drug inhibiting activation of NEDD8, has shown a significant therapeutic effect in four Phase I clinical cancer trials in 2015-2016. These include pevonedistat trials against acute myeloid leukemia and myelodysplastic syndromes,^[14] relapsed/refractory multiple myeloma or lymphoma,^[15] metastatic melanoma,^[16] and advanced solid tumors.^[17]

In preclinical studies

PPARγ neddylation

PPARγ has a crucial role in adipogenesis and lipid accumulation within adipocytes (fat cells).^[18] Activated NEDD8 stabilizes PPARγ, allowing increased adipogenesis. In experiments with mice, Pevonedistat, a drug inhibiting activation of NEDD8, prevented high-fat diet-induced obesity and glucose intolerance.^[18]

NF-κB and NEDD8

The transcriptional activity of NF-κB is primarily regulated by physical interaction with inhibitory IκB proteins (IκBα and IκBβ), which prevents its nuclear translocation.^[19] Degradation of the IκBα subunit of IκB is mediated by ubiquitination, and this ubiquitination depends on neddylation.^[20] Pevonedistat (MLN4924) inhibits activation of NEDD8, that then inhibits ubiquitination of IκBα, and this inhibits NF-κB translocation to the nucleus.^[19]

Pevonedistat, through its effects on NF-κB and a target of NF-κB (microRNA-155), prolonged the survival of mice engrafted with leukemic cells.^[19]

Colorectal cancer

Inhibition of NEDD8 activation by pevonedistat was found to induce growth arrest and apoptosis in 16/122 (13%)

References