Deficiency of nucleotide excision repair is associated with mutational signature observed in cancer
Deficiency of nucleotide excision repair is associated with mutational signature observed in cancer
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DOI：
10.1101/gr.246223.118
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发表时间：
2019-07-01
期刊：
影响因子：
7
通讯作者：
Cuppen, Edwin
中科院分区：
文献类型：
--
作者：
Jager, Myrthe;Blokzijl, Francis;Cuppen, Edwin
核苷酸切除修复（NER）是保护细胞免受基因组损伤的主要DNA修复途径之一。这一途径的中断可能会导致癌症的发展和加速衰老。NER缺陷的突变特征可能揭示重要的诊断机会，因为NER缺陷的肿瘤对某些治疗更敏感。在这里，我们分析了全基因组的成体干细胞（ASC）从NER缺陷Erccl（-/Delta）小鼠的体细胞突变谱。我们的研究结果表明，在肝脏中，但不是在小肠ASCs，这与在这些小鼠中观察到的组织特异性衰老病理学的基础上，NER-deficiency增加了两倍的替代负荷。此外，两种组织的NER缺陷型ASC显示出Signature 8突变的贡献增加，这是一种在各种癌症类型中反复观察到的病因不明的突变模式。分散的基因组分布的碱基取代表明，缺乏全球基因组NER（GG-NER）的基础上观察到的突变后果。与此一致，我们观察到GG-NER缺陷型人类类器官培养物中Signature 8突变增加，其中使用CRISPR-Cas9基因编辑删除XPC。此外，NER缺陷乳腺肿瘤的基因组显示与NER熟练肿瘤相比，Signature 8突变的贡献增加。因此，基于患者的突变谱，Signature 8突变水平的升高可能有助于预测NER缺陷。
Nucleotide excision repair (NER) is one of the main DNA repair pathways that protect cells against genomic damage. Disruption of this pathway can contribute to the development of cancer and accelerate aging. Mutational characteristics of NER-deficiency may reveal important diagnostic opportunities, as tumors deficient in NER are more sensitive to certain treatments. Here, we analyzed the genome-wide somatic mutational profiles of adult stem cells (ASCs) from NER-deficient Erccl(-/Delta) mice. Our results indicate that NER-deficiency increases the base substitution load twofold in liver but not in small intestinal ASCs, which coincides with the tissue-specific aging pathology observed in these mice. Moreover, NER-deficient ASCs of both tissues show an increased contribution of Signature 8 mutations, which is a mutational pattern with unknown etiology that is recurrently observed in various cancer types. The scattered genomic distribution of the base substitutions indicates that deficiency of global-genome NER (GG-NER) underlies the observed mutational consequences. In line with this, we observe increased Signature 8 mutations in a GG-NER-deficient human organoid culture, in which XPC was deleted using CRISPR-Cas9 gene-editing. Furthermore, genomes of NER-deficient breast tumors show an increased contribution of Signature 8 mutations compared with NER-proficient tumors. Elevated levels of Signature 8 mutations could therefore contribute to a predictor of NER-deficiency based on a patient's mutational profile.