Contents

### **Preface XI**


Preface

Genome integrity is maintained through a sophisticated series of mechanisms that are able to detect early, signal for, and repair DNA damage. This is termed DNA damage response (DDR) and it is crucial for survival and propagation of life. As these procedures should take place quite rapidly in order to halt cell division, or noncanonical gene expression, there is no time, in most cases, for new synthesis of factors responsible for DDR and repair. An apparent solution is recruitment by the cell of factors from other ongoing processes, reprioritizing needs, and restoring DNA damage by modifying existing molecules and their subsequent function. Signaling leading to conformational changes and affecting protein-DNA and pro‐

tein-protein interactions is a very effective cellular strategy toward achieving this goal.

Likewise, phosphorylation, ubiquitination/ubiquitylation (the covalent link of one or more ubiquitously found ubiquitin molecules, by a wide variety of linear or chain creating mono- or polymer forms on mainly lysine residues of a target protein) in conjunction with the less stud‐ ied SUMOylation, emerged to be critical players in regulating numerous eukaryotic cellular processes including DDR and repair pathways, cell cycle control, and cell fate decisions. Cu‐ mulative studies reveal that ubiquitination is implicated in a broad range of molecular func‐ tions that may lead to the alteration of protein stability and homeostasis, subcellular localization, or function assignment through interaction with other protein partners. It seems that different ubiquitin linkages, directing target proteins to either proteasomal degradation or conformational and thus functional modifications, cooperate to orchestrate genomic stabil‐ ity maintenance through a finely tuned dynamic function of both ubiquitin (ub) conjugating enzymes (E1, 2 and 3 types of ub ligases) and ub removal enzymes (Deubiquitinases, Dubs). DDR consists of lesion type and magnitude recognition (sensing) due to either endogenous or exogenous causes, followed by signaling that activates the responsible mediators, come‐ diators, and effectors in order to halt the cell cycle and local transcription, until efficient re‐ pair of the damage is performed and verified by the most reliable and rapid pathway available in the given cell cycle stage. This overcomes the replication stress/collapsed forks and promotes the restart of replication synthesis and this is followed, when effectively re‐ paired, by cell cycle progression. Accordingly, repair of serious genotoxic insults, like dou‐ ble strand breaks (DSBs), functions through a platform capable of correcting these deleterious lesions and ensuring genome integrity. In all of these steps, protein modification by ubiquitination and SUMO consists of a crucial regulatory process that when impaired may result in aging, tumorigenesis, and other life-threatening conditions. Another impor‐ tant aspect to consider is genome architecture and the role of chromatin remodeling through ubiquitination, facilitating DDR and providing access to repair mechanisms, processes tight‐ ly interlinked and intercommunicating in order to handle and remove toxic DNA lesions.

