A network of DNA damage response (DDR) mechanisms protects organisms against the continuous genotoxic stress induced by reactive metabolites and other genotoxic agents, such as environmental contaminants and ultraviolet (UV) radiation from the sun 
. The DDR network consists of several DNA repair mechanisms, cell cycle checkpoints and cellular senescence and apoptotic signaling cascades. Nucleotide Excision Repair (NER) is a DNA repair mechanism that is able to remove a wide variety of helix-destabilizing DNA lesions including those induced by UV light.
Eukaryotic NER is a highly conserved multi-step process, involving more than 25 proteins, of which the principal molecular mechanism has been dissected in detail 
. NER is initiated by two distinct DNA damage recognition mechanisms which use the same machinery to repair the damage. Damage in the transcribed strand of active genes is repaired by Transcription Coupled Repair (TCR), which depends on recruitment of the ATP-dependent chromatin remodeling protein Cockayne Syndrome protein B (CSB) and the WD40 domain containing protein Cockayne Syndrome protein A (CSA) to the site of damage 
. TCR is thought to be activated by stalling of elongating RNA polymerase II during transcription 
. Damage in other, non-transcribed sequences of the genome is repaired by Global Genome Repair (GGR), which requires detection of the lesions by the UV-damaged DNA-binding protein (UV-DDB) complex and a complex containing Xeroderma Pigmentosum group C protein (XPC), human homolog of RAD23 (hHR23) and Centrin-2 
. The XPC protein is essential for the initiation of GGR and subsequent recruitment of other NER factors 
. The majority of XPC is found in complex with the hHR23B protein, while only a fraction copurifies with the redundant hHR23A protein. Both hHR23 proteins are thought to stabilize XPC and stimulate its function 
. Although HR23B is not essential for in vitro
NER, in vivo
damage is poorly repaired in cells lacking hHR23B 
, indicating that hHR23B is essential for proper NER function. Following detection of a lesion, either via GGR or TCR, the transcription factor IIH (TFIIH) is recruited to open the DNA helix around the damage in an ATP-dependent manner using its Xeroderma Pigmentosum group B and D (XPB and XPD) helicase subunits 
. Next, Xeroderma Pigmentosum group A (XPA) and Replication Protein A (RPA) are recruited to stabilize the repair complex and properly orient the structure-specific endonucleases Xeroderma Pigmentosum group F (XPF)/Excision Repair Cross-Complementing protein 1 (ERCC1) and Xeroderma Pigmentosum group G (XPG) to excise the damaged strand. The resulting ~30 nt single strand DNA gap is filled by DNA synthesis and ligation.
In mammals, congenital defects in GGR and TCR lead to an increased sensitivity towards DNA damaging agents such as UV irradiation. Inherited mutations in GGR genes cause Xeroderma Pigmentosum, which is characterized by extreme UV-sensitivity and skin cancer predisposition 
. Hereditary TCR deficiency causes Cockayne syndrome, which leads to entirely different features such as severe but variable neurodevelopmental symptoms and premature aging. In contrast to mammals, specific TCR defects in yeast have only a marginal effect on DNA damage resistance, despite a relatively larger proportion of the genome that is transcriptionally active 
Current knowledge of NER does not provide an explanation for the pleiotropic phenotypic expression of NER-deficiencies. Despite detailed insight in the molecular mechanism of NER, many aspects of the in vivo
UV-induced DNA damage response (UV-DDR) are still unclear. It is for instance not well understood how NER functions in nucleosomal DNA and in different tissues of developing organisms. Therefore, a full understanding of the complete UV-DDR and its interplay with NER in living organisms is imperative. The nematode C. elegans
seems well suited to analyze the complete UV-DDR in vivo
in more detail, because of its short lifetime, well-characterized biology and its amenable use to identify new genes involved in the UV-DDR. Several studies have specifically addressed the role of NER proteins in the UV-DDR in C. elegans
. Knockdown of the C. elegans
orthologs of mammalian CSB, XPA and XPF increases sensitivity to UV irradiation 
. Furthermore, it was shown that the XPA and XPC orthologs function in the C. elegans
germ line to induce cell cycle arrest and apoptosis in response to UV irradiation 
. Together, these studies suggest that NER function is highly conserved in C. elegans
. However, a thorough analysis of the function of NER and, more specifically, the role of the GGR and TCR subpathways in response to UV irradiation in different tissues during development has not been performed.
In this study, we make use of mutations in the C. elegans RAD23, XPC and CSB orthologs to show that during early development, in germ cells and embryos, GGR is the major pathway involved in the response to UV irradiation. Defective GGR leads to inefficient lesion removal in germ cells, specific defects in germ cell development and embryonic death after UV irradiation. Intriguingly, in juvenile and adult animals TCR is the major NER pathway involved in the UV response. Analysis of the UV response of embryos shows that, during development, TCR gradually becomes more important than GGR. Finally, we exploit C. elegans to identify novel genes involved in the UV-DDR, specifically in the TCR-related UV response. Our results reveal four genes implicated in SWI/SNF and four genes implicated in ISWI ATP-dependent chromatin remodeling whose involvement in the UV-DDR changes during development.