Nuclear translocation and entry Sample Clauses

Nuclear translocation and entry. The last physical barrier to nucleic acid delivery is translocation to, and entry into, the nucleus. Overcoming this barrier is only necessary for pDNA, which unlike siRNA that exerts its effects in the cytoplasm requires entry into the nucleus in order to be transcribed. The stability of DNA in the cytoplasm is threatened by the presence of nucleases (Lechardeur, D. et al., 1999). It is thus not surprising that the nuclear translocation efficiency of pDNA is low with an estimate of 1 of 1000 plasmids making it into the nucleus (Xxxxxxx, X. et al., 1998). Endocytosis may play a role in the transport of DNA from near the plasma membrane to the perinuclear zone. Another possibility is that the positively charged lipoplex-containing endosomes might interact and eventually fuse with the endoplasmic reticulum resulting in the release of DNA into the lumen of the reticulum. The DNA could then easily access the nucleus through the continuous network existing between nuclear and reticulum membranes. Xxxxxx et al (2002) suggested that complexes delivered into the cytoplasm of cells fused directly with the nuclear membrane to release DNA into the nucleus. In terms of nuclear entry, the nuclear membrane is known to contain highly regulated transport structures known as nuclear pores with a diameter of approximately 25 nm. The small diameter of the pores is expected to constrain the entry of pDNA as only small molecules (≤40 KDa) can enter via passive diffusion through the nuclear pores. Therefore two pathways for nuclear entry have been proposed; either via a passive entry into the nucleus during cell division when the nuclear membrane is temporarily disintegrated (Xxxxxxx, X. et al., 2001) or via an active transport of DNA through the nuclear pores (Xxxxx, P. et al., 1999).