No abstract

DNA is subjected to several modifications, resulting from endogenous and exogenous sources. The cell has developed a network of complementary DNA-repair mechanisms, and in the human genome, >130 genes have been found to be involved. Knowledge about the basic mechanisms for DNA repair has revealed an unexpected complexity, with overlapping specificity within the same pathway, as well as extensive functional interactions between proteins involved in repair pathways. Unrepaired or improperly repaired DNA lesions have serious potential consequences for the cell, leading to genomic instability and deregulation of cellular functions. A number of disorders or syndromes, including several cancer predispositions and accelerated aging, are linked to an inherited defect in one of the DNA-repair pathways. Genomic instability, a characteristic of most human malignancies, can also arise from acquired defects in DNA repair, and the specific pathway affected is predictive of types of mutations, tumor drug sensitivity, and treatment outcome. Although DNA repair has received little attention as a determinant of drug sensitivity, emerging knowledge of mutations and polymorphisms in key human DNA-repair genes may provide a rational basis for improved strategies for therapeutic interventions on a number of tumors and degenerative disorders.

Abbreviations used: 1α,25-(OH) 2 D 3 -1α,25-dihydroxycholecalciferol and calcitriol; APE/Ref-1 -apurinic (apyrimidinic) endonuclease/redox-factor 1; CRP -C-reactive protein; ER -endoplasmic reticulum; ERAD endoplasmic reticulum associated protein degradation; mTORC -mammalian target of rapamycin complex; PDI -protein disulfide isomerase; PKC -protein kinases C; PLA 2 -phospholipases A 2 ; Plc -peptide loading complex; PLC -phospholipase C; PrP SC -scrapie prion protein (misfolded prions); STAT -signal transducer and activator of transcription; STAT3 -signal transducer and activator of transcription 3; SV40 virus -simian virus 40; VDR -vitamin D receptor Review ERp57/GRP58: A PROTEIN WITH MULTIPLE FUNCTIONSCARLO TURANO*, ELISA GAUCCI, CATERINA GRILLO and SILVIA CHICHIARELLI Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Scienze Biochimiche "A. Rossi Fanelli", Sapienza -Università di Roma, Italy Abstract: The protein ERp57/GRP58 is a stress-responsive protein and a component of the protein disulfide isomerase family. Its functions in the endoplasmic reticulum are well known, concerning mainly the proper folding and quality control of glycoproteins, and participation in the assembly of the major histocompatibility complex class 1. However, ERp57 is present in many other subcellular locations, where it is involved in a variety of functions, primarily suggested by its participation in complexes with other proteins and even with DNA. While in some instances these roles need to be confirmed by further studies, a great number of observations support the participation of ERp57 in signal transduction from the cell surface, in regulatory processes taking place in the nucleus, and in multimeric protein complexes involved in DNA repair.

Protein disulfide isomerase ERp57 is localized predominantly in the endoplasmic reticulum, but is also present in the cytosol and, according to preliminary evidence, in the nucleus of avian cells. Conclusive evidence of its nuclear localization and of its interaction with DNA in vivo in mammalian cells is provided here on the basis of DNA-protein cross-linking experiments performed with two different cross-linking agents on viable HeLa and 3T3 cells. Nuclear ERp57 could also be detected by immunofluorescence in HeLa cells, where it showed an intracellular distribution clearly different from that of an homologous protein, located exclusively in the endoplasmic reticulum. Mammalian ERp57 resembles the avian protein in its recognition of S/MAR-like DNA sequences and in its association with the nuclear matrix. It can be hypothesized that ERp57, which is known to associate with other proteins, in particular STAT3 and calreticulin, may contribute to their nuclear import, DNA binding, or other functions that they fulfil inside the nucleus.