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      Involvement of Global Genome Repair, Transcription Coupled Repair, and Chromatin Remodeling in UV DNA Damage Response Changes during Development

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          Nucleotide Excision Repair (NER), which removes a variety of helix-distorting lesions from DNA, is initiated by two distinct DNA damage-sensing mechanisms. Transcription Coupled Repair (TCR) removes damage from the active strand of transcribed genes and depends on the SWI/SNF family protein CSB. Global Genome Repair (GGR) removes damage present elsewhere in the genome and depends on damage recognition by the XPC/RAD23/Centrin2 complex. Currently, it is not well understood to what extent both pathways contribute to genome maintenance and cell survival in a developing organism exposed to UV light. Here, we show that eukaryotic NER, initiated by two distinct subpathways, is well conserved in the nematode Caenorhabditis elegans. In C. elegans, involvement of TCR and GGR in the UV-induced DNA damage response changes during development. In germ cells and early embryos, we find that GGR is the major pathway contributing to normal development and survival after UV irradiation, whereas in later developmental stages TCR is predominantly engaged. Furthermore, we identify four ISWI/Cohesin and four SWI/SNF family chromatin remodeling factors that are implicated in the UV damage response in a developmental stage dependent manner. These in vivo studies strongly suggest that involvement of different repair pathways and chromatin remodeling proteins in UV-induced DNA repair depends on developmental stage of cells.

          Author Summary

          Nucleotide Excision Repair (NER) removes many forms of helix-distorting DNA damage which interfere with transcription and replication, including those induced by UV irradiation. NER is initiated when damage is sensed during transcription, i.e. Transcription-Coupled Repair (TCR), or when damage is sensed in non-transcribed genomic sequences, i.e. Global Genome Repair (GGR). Although the molecular mechanism of the core NER is known, it is not well understood how the UV response functions in living organisms and which additional mechanisms are involved to regulate its efficiency. Therefore, we exploited the small soil nematode C. elegans to study the UV response in a living organism. Using different NER–deficient animals, we found that in early development mainly GGR, but in later development mainly TCR is active in the UV response. Furthermore, we identified several new chromatin remodeling factors, whose involvement in the UV response also differs during development and which are thought to regulate efficiency of the UV response by altering chromatin structure. Our studies show that C. elegans is very well suited to genetically analyze the UV response during different developmental stages and in different tissues in a living animal.

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          Most cited references 57

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          A conserved checkpoint pathway mediates DNA damage--induced apoptosis and cell cycle arrest in C. elegans.

          To maintain genomic stability following DNA damage, multicellular organisms activate checkpoints that induce cell cycle arrest or apoptosis. Here we show that genotoxic stress blocks cell proliferation and induces apoptosis of germ cells in the nematode C. elegans. Accumulation of recombination intermediates similarly leads to the demise of affected cells. Checkpoint-induced apoptosis is mediated by the core apoptotic machinery (CED-9/CED-4/CED-3) but is genetically distinct from somatic cell death and physiological germ cell death. Mutations in three genes--mrt-2, which encodes the C. elegans homolog of the S. pombe rad1 checkpoint gene, rad-5, and him-7-block both DNA damage-induced apoptosis and cell proliferation arrest. Our results implicate rad1 homologs in DNA damage-induced apoptosis in animals.
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            Genetic control of programmed cell death in the Caenorhabditis elegans hermaphrodite germline.

            Development of the nematode Caenorhabditis elegans is highly reproducible and the fate of every somatic cell has been reported. We describe here a previously uncharacterized cell fate in C. elegans: we show that germ cells, which in hermaphrodites can differentiate into sperm and oocytes, also undergo apoptotic cell death. In adult hermaphrodites, over 300 germ cells die, using the same apoptotic execution machinery (ced-3, ced-4 and ced-9) as the previously described 131 somatic cell deaths. However, this machinery is activated by a distinct pathway, as loss of egl-1 function, which inhibits somatic cell death, does not affect germ cell apoptosis. Germ cell death requires ras/MAPK pathway activation and is used to maintain germline homeostasis. We suggest that apoptosis eliminates excess germ cells that acted as nurse cells to provide cytoplasmic components to maturing oocytes.
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              Cockayne syndrome A and B proteins differentially regulate recruitment of chromatin remodeling and repair factors to stalled RNA polymerase II in vivo.

              Restoration of UV-inhibited transcription requires removal of transcription-blocking DNA lesions by transcription-coupled repair (TCR). In mammals, TCR is dependent on CSA and CSB proteins; however, their functions are largely unknown. Here, we analyzed the composition of UV-stalled transcription elongation complexes from human cells. We show that CSB and CSA display differential roles in recruitment of TCR-specific factors and that assembly for TCR occurs without disruption of the UV-stalled RNA polymerase II (RNAPIIo). CSB fulfills a key role as a coupling factor to attract histone acetyltransferase p300, nucleotide excision repair (NER) proteins, and CSA-DDB1 E3-ubiquitin ligase complex with the COP9 signalosome. CSA is dispensable for attraction of NER proteins to lesion-stalled RNAPIIo, yet in cooperation with CSB is required to recruit XAB2, the nucleosomal binding protein HMGN1, and TFIIS. These results give insight into the nature and order of molecular events that take place during TCR in the context of chromosomal DNA.

                Author and article information

                Role: Editor
                PLoS Genet
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                May 2010
                May 2010
                6 May 2010
                : 6
                : 5
                [1 ]Department of Genetics, Medical Genetics Center, Erasmus MC, Rotterdam, The Netherlands
                [2 ]Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany
                [3 ]Department of Cell Biology, Medical Genetics Center, Erasmus MC, Rotterdam, The Netherlands
                University of Washington, United States of America
                Author notes

                Conceived and designed the experiments: HL WV. Performed the experiments: HL JAM BS. Analyzed the data: HL WV. Contributed reagents/materials/analysis tools: HL GJ. Wrote the paper: HL JAM BS JHJH GJ WV.

                Lans et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 15
                Research Article
                Cell Biology/Cellular Death and Stress Responses
                Developmental Biology
                Genetics and Genomics/Gene Discovery
                Molecular Biology/DNA Repair



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