Preface

It has been over three decades since the modification of proteins by covalent attachment (primarily to lysine residues) of the small, 76 amino acid protein ubiquitin, and the ability of this modification to target proteins for destruction by a protease, now known as the 26S proteasome, was first discovered. Subsequent discoveries of an E1 ubiquitin-activating enzyme, E2 ubiquitin-conjugating enzymes, and E3 ubiquitin ligases that function as an enzymatic cascade culminating in the ubiquitination of substrates revealed that the vast majority of protein degradation depends on this ubiquitin proteasome system (UPS). Today, the human UPS is comprised of nearly 1000 proteins and has expanded beyond ubiquitin to include ubiquitinlike modifiers (UBLs, including SUMOs, NEDD8, ATG8, ATG12, URM1, UFM1, FAT10, HUB1, and ISG15), a handful of E1s, tens of E2s, hundreds of E3s, nearly 100 deubiquitinating enzymes, and UBL-specific interacting proteins that regulate the UBL-modified proteasome within our cells. Not surprisingly, the pathways that comprise the UPS rely on the coordinated activities of multiple pathways.

Indeed, the canonical protein turnover function of the UPS is a highly dynamic process that is regulated on multiple levels. For example, E3 ligases, which provide substrate specificity within the system, may be regulated at the level of expression both transcriptionally and at the protein level by ubiquitination-mediated degradation that may be self-catalyzed or mediated by an antagonistic E3. For some multisubunit E3s the formation of an active holoenzyme is regulated by posttranslational modification, including phosphorylation and conjugation of the UBL NEDD8. Once the E3 is present in the cell, its ability to recognize substrates may be regulated by posttranslational modification of the substrate, while the ability to ubiquitinate the substrate may be further regulated by the expression or modification of the cognate E2 enzyme. Then, once ubiquitinated, the fate of a substrate destined for the proteasome is still not sealed because the modification may be removed by deubiquitinating enzymes or its delivery to the proteasome may be regulated by the modification or availability of ubiquitin receptors.

 Conjugation with ubiquitin itself is also a multifaceted modification and we now know that degradation is but one outcome resulting from the covalent addition of ubiquitin to a protein. It is now accepted that polyubiquitin linkages occur via all of seven lysines of ubiquitin, branched heterotypic chains, as well as linear ubiquitin modifications and monoubiquitination. Although the roles of some of these modifications are not yet well established, monoubiquitination of histones has emerged as an important feature of the "histone code," and regulating many chromatin-related processes and K63-linked polyubiquitin chains is a fundamental part of many signaling pathways. In addition to the diversity of ubiquitin signals created by specific linkages, posttranslational modification of ubiquitin, including phosphorylation, acetylation, and ADP-ribosylation, have recently been shown to impact chain stability and chain elongation, among other effects.

In keeping with the diversity of the components within the UPS, we now know that the UPS mediates central signaling events in myriad processes involved in both cellular and organismal health and homeostasis. For example, numerous pathways

within the UPS are implicated in disease, ranging from cancer to neurodegenerative diseases such as Parkinson's. An in-depth understanding of these signaling cascades will significantly enhance our knowledge of their pathological roles while identifying potential therapeutic targets.

It would require a veritable encyclopedia of review articles to fully encompass the current view of UPS research. The goal of this book is to deliver a collection of synopses of current areas of UPS research that highlight the importance of understanding the biology of the UPS to identify disease-relevant pathways, and the need to elucidate the molecular machinations within the UPS to develop methods for therapeutic modulation of these pathways. Specifically, the chapters of this book provide up-to-date views on cellular regulation in the context of control of the cell cycle by ubiquitin-mediated proteolysis, the role of ubiquitin-modified chromatin in DNA repair, and transcriptional elongation and mitotic bookmarking of epigenetic information during mitosis. The UPS is also examined from a disease perspective with regard to altered E3 activities in cancer (including developing therapeutic strategies), the role of K63-linked polyubiquitin in multiple disease settings, and the role of UCHL1 in Parkinson's disease. Current snapshots of several molecular aspects of the UPS are also provided in discussions of how cells discriminate between ubiquitin and UBLs, regulation of proteasome function by ubiquitin, the function of B-box domains in ubiquitin ligases, and regulation of ubiquitin ADPribosylation. The poignant overviews encompassed within this book are provided by researchers at the forefronts of their respective areas and are intended to serve as an informative primer for researchers who are new to the field and as a concise state of the research for those who are already entrenched in the field of ubiquitin.

> **Matthew K. Summers**  The Ohio State University, Department of Radiology and Comprehensive Cancer Center, Columbus, OH, USA

Section 1
