cerevisiae DOA1 UFD3, is phos pholipase A2 activating protein, that has been implicated in a variety of biological processes that involve the Ub system. In particular, it has been linked to the maintenance of Ub levels, but the mechanism by which it accomplishes this is unclear. selleck chemicals Interestingly, it has been recently demonstrated that human PLAA enhances cisplatin induced apoptosis in HeLa cells. Transcriptional induction of PLAA by cisplatin can potentially promote cytotoxicity through phospholipase A2 activation and arachidonic acid accumulation. Interestingly, carbopla tin sensitive cells from ovarian cancer patients expressed higher levels of PLAA than their resistant counterparts. The C terminal domain of PLAA binds p97 Cdc48, an AAA ATPase which, among other functions, helps in transferring ubiquitinated proteins to the proteasome for degradation.

In addition, PLAA is also asso ciated with HDAC6, a unique cytoplasmic deacetylase capable of interacting with Ub and a master regulator of the cell protective response to cytotoxic protein aggre gate formation. Conclusions To maintain the genome, cells have evolved multiple pathways to detect and respond to DNA damage. The cellular response to DNA damage has been particularly well characterized in the fission yeast S. pombe. An important way in which various organisms coordi nate facets of the DNA damage response is the post translational modification of proteins. While phos phorylation has received a great deal of attention, it has become increasingly clear that other types of post trans lational modifications, such as ubiquitination, also play critical roles.

Ub is an essential modifier conserved in all eukaryotes from yeast to human and existing in sev eral cellular compartments. During normal growth, a significant portion of Ub is used to target proteins for proteasomal degradation, and it is presumably seques tered within these pathways. However, in the presence of DNA damage, Ub must be quickly made available for post translational modification of proteins involved in sensing, repairing, and or tolerating the damage. The present study supports that specific proteasome genes can contribute differently to cisplatin response. Only a few of yeast genes appear to regulate sensitivity per se suggesting pathway redun dancy.

The prospective identification of novel targets for modulation of cisplatin sensitivity in an eukaryotic model organism appeared particularly intriguing towards the discovery of strategies to overcome cisplatin resis Batimastat tance in human tumors. In principle, a variety of approaches may be employed in an attempt to sensitize cancer cells to cisplatin. In the context of the Ub proteasome pathway, the develop ment of small molecules is still at an early stage, but some research groups are already looking at attacking components of the Ub proteasome pathway.