DNA repair mechanisms in dividing and non-dividing cells

DNA damage created by endogenous or exogenous genotoxic agents can exist in multiple forms, and if allowed to persist, can promote genome instability and directly lead to various human diseases, particularly cancer, neurological abnormalities, immunodeficiency and premature aging. To avoid such deleterious outcomes, cells have evolved an array of DNA repair pathways, which carry out what is typically a multiple-step process to resolve specific DNA lesions and maintain genome integrity. To fully appreciate the biological contributions of the different DNA repair systems, one must keep in mind the cellular context within which they operate. For example, the human body is composed of non-dividing and dividing cell types, including, in the brain, neurons and glial cells. We describe herein the molecular mechanisms of the different DNA repair pathways, and review their roles in non-dividing and dividing cells, with an eye toward how these pathways may regulate the development of neurological disease.     

XPC: Going where no DNA damage sensor has gone before

XPC has long been considered instrumental in DNA damage recognition during global genome nucleotide excision repair (GG-NER). While this recognition is crucial for organismal health and survival, as XPC’s recognition of lesions stimulates global genomic repair, more recent lines of research have uncovered many new non-canonical pathways in which XPC plays a role, such as base excision repair (BER), chromatin remodeling, cell signaling, proteolytic degradation, and cellular viability. Since the first discovery of its yeast homolog, Rad4, the involvement of XPC in cellular regulation has expanded considerably. Indeed, our understanding appears to barely scratch the surface of the incredible potential influence of XPC on maintaining proper cellular function. Here, we first review the canonical role of XPC in lesion recognition and then explore the new world of XPC function.     

A C. elegans homolog of the Cockayne syndrome complementation group A gene

Cockayne syndrome (CS) is a debilitating and complex disorder that results from inherited mutations in the CS complementation genes A and B, CSA and CSB. The links between the molecular functions of the CS genes and the complex pathophysiology of CS are as of yet poorly understood and are the subject of intense debate. While mouse models reflect the complexity of CS, studies on simpler genetic models might shed new light on the consequences of CS mutations. Here we describe a functional homolog of the human CSA gene in Caenorhabditis elegans. Similar to its human counterpart, mutations in the nematode csa-1 gene lead to developmental growth defects as a consequence of DNA lesions.     

The emerging role of deubiquitination in nucleotide excision repair

Nucleotide excision repair (NER) protects genome stability by eliminating DNA helix distorting lesions, such as those induced by UV radiation. The addition and removal of ubiquitin, namely, ubiquitination and deubiquitination, have recently been demonstrated as general mechanisms to regulate protein functions. Accumulating evidence shows that several NER factors are subjected to extensive regulation by ubiquitination and deubiquitination. Thus, the balance between E3 ligases and deubiquitinating enzyme activities can dynamically alter the ubiquitin landscape at DNA damage sites, thereby regulating NER efficiency. Current knowledge about XPC ubiquitination by different ubiquitin E3 ligases highlights the importance of ubiquitin linkage types in regulating XPC binding and release from damaged DNA. Here, we discuss the emerging roles of deubiquitinating enzymes and their ubiquitin linkage specificities in NER.