DNA interstrand crosslinks (ICLs) are generated by endogenous sources and chemotherapeutics, and pose a threat to genome stability and cell survival. Using Caenorhabditis elegans mutants, we identify DNA repair factors that protect against the genotoxicity of ICLs generated by trioxsalen/ultraviolet A (TMP/UVA) during development and aging. Mutations in nucleotide excision repair (NER) components (e.g. XPA-1 and XPF-1) imparted extreme sensitivity to TMP/UVA relative to wild-type animals, manifested as developmental arrest, defects in adult tissue morphology and functionality, and shortened lifespan. Compensatory roles for global-genome (XPC-1) and transcription-coupled (CSB-1) NER in ICL sensing were exposed. The analysis also revealed contributions of homologous recombination (BRC-1/BRCA1), the MUS-81, EXO-1, SLX-1 and FAN-1 nucleases, and the DOG-1 (FANCJ) helicase in ICL resolution, influenced by the replicative-status of the cell/tissue. No obvious or critical role in ICL repair was seen for non-homologous end-joining (cku-80) or base excision repair (nth-1, exo-3), the Fanconi-related proteins BRC-2 (BRCA2/FANCD1) and FCD-2 (FANCD2), the WRN-1 or HIM-6 (BLM) helicases, or the GEN-1 or MRT-1 (SNM1) nucleases. Our efforts uncover replication-dependent and -independent ICL repair networks, and establish nematodes as a model for investigating the repair and consequences of DNA crosslinks in metazoan development and in adult post-mitotic and proliferative germ cells.

中文翻译：

---

秀丽隐杆线虫发育和衰老过程中DNA交联修复途径的系统分析

DNA链间交联（ICL）由内源性和化学疗法产生，对基因组稳定性和细胞存活构成威胁。使用秀丽隐杆线虫突变体，我们确定了DNA修复因子，可防止在发育和衰老过程中由Trioxsalen /紫外线A（TMP / UVA）产生的ICL的遗传毒性。核苷酸切除修复（NER）组件（例如XPA-1和XPF-1）的突变相对于野生型动物对TMP / UVA具有极高的敏感性，表现为发育停滞，成年组织形态和功能缺陷以及寿命缩短。暴露了在ICL传感中全局基因组（XPC-1）和转录偶联（CSB-1）NER的补偿作用。分析还揭示了同源重组（BRC-1 / BRCA1），MUS-81，EXO-1，SLX-1和FAN-1核酸酶以及DOG-1（FANCJ）解旋酶在ICL分辨率中的作用，受到细胞/组织的复制状态。cku-80）或碱基切除修复（nth-1，exo-3），Fanconi相关蛋白BRC-2（BRCA2 / FANCD1）和FCD-2（FANCD2），WRN-1或HIM-6（BLM）解旋酶或GEN-1或MRT-1（SNM1）核酸酶。我们的工作揭示了依赖复制和不依赖复制的ICL修复网络，并建立了线虫作为研究后生动物发育以及成年有丝分裂和增殖后生殖细胞中DNA交联的修复和后果的模型。