Involvement of global genome repair, transcription coupled repair, and chromatin remodeling in UV DNA damage response changes during development.
Involvement of global genome repair, transcription coupled repair, and chromatin remodeling in UV DNA damage response changes during development.
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DOI：
10.1371/journal.pgen.1000941
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发表时间：
2010-05-06
期刊：
影响因子：
4.5
通讯作者：
Vermeulen W
中科院分区：
文献类型：
--
作者：
Lans H;Marteijn JA;Schumacher B;Hoeijmakers JH;Jansen G;Vermeulen W
核苷酸切除修复 (NER) 可从 DNA 中去除各种螺旋扭曲损伤，由两种不同的 DNA 损伤传感机制启动。转录耦合修复 (TCR) 可消除转录基因活性链的损伤，并依赖于 SWI/SNF 家族蛋白 CSB。全局基因组修复 (GGR) 可消除基因组其他位置存在的损伤，并依赖于 XPC/RAD23/Centrin2 复合物的损伤识别。目前，尚不清楚这两种途径在多大程度上有助于暴露于紫外线的发育中的生物体的基因组维持和细胞存活。在这里，我们表明，由两种不同的亚途径启动的真核 NER 在内线虫秀丽隐杆线虫中得到了很好的保守。在秀丽隐杆线虫中，TCR 和 GGR 在紫外线诱导的 DNA 损伤反应中的参与在发育过程中发生了变化。在生殖细胞和早期胚胎中，我们发现 GGR 是紫外线照射后促进正常发育和存活的主要途径，而在发育后期，TCR 主要发挥作用。此外，我们还确定了四种 ISWI/Cohesin 和四种 SWI/SNF 家族染色质重塑因子，它们以发育阶段依赖的方式参与紫外线损伤反应。这些体内研究强烈表明，紫外线诱导的 DNA 修复中不同修复途径和染色质重塑蛋白的参与取决于细胞的发育阶段。核苷酸切除修复 (NER) 可消除多种形式的螺旋扭曲 DNA 损伤，这些损伤会干扰转录和复制，包括由紫外线照射引起的损伤。当转录过程中检测到损伤时，即转录偶联修复 (TCR)，或在非转录基因组序列中检测到损伤时，即全局基因组修复 (GGR)，NER 就会启动。尽管核心 NER 的分子机制已为人所知，但尚不清楚紫外线响应如何在活生物体中发挥作用，以及涉及哪些其他机制来调节其效率。因此，我们利用小型土壤线虫秀丽隐杆线虫来研究活生物体的紫外线响应。使用不同的NER缺陷动物，我们发现在早期发育中主要是GGR，但在后期发育中主要是TCR在UV反应中活跃。此外，我们还发现了几种新的染色质重塑因子，它们对紫外线响应的参与在发育过程中也有所不同，并且被认为通过改变染色质结构来调节紫外线响应的效率。我们的研究表明，线虫非常适合对活体动物不同发育阶段和不同组织的紫外线反应进行基因分析。
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. 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.