英国威康桑格研究所Peter J. Campbell研究组发现，突变性DNA损伤在体细胞中的长期持久性。该研究于2025年1月15日在线发表于国际一流学术期刊《自然》。

研究人员使用来自89个供体的高分辨率系统发育树，识别了在来自血液、肝脏和支气管上皮的正常人类干细胞中，818个DNA损伤引发的突变，这些损伤在多个细胞周期中持续存在。持续的DNA损伤发生率较高，且具有独特的突变特征，在接触烟草或化疗的供体中尤为明显，表明这些损伤可能源自外源性致突变物。

在造血干细胞中，持续性的DNA损伤，可能来自内源性来源，生成了特征性的突变标志SBS19；这种损伤在整个生命周期中持续存在，包括在宫内；并且平均持续了2.2年，其中15-25%的损伤至少持续了3年。

研究人员估计，平均而言，造血干细胞在任何时刻大约有八个此类损伤，其中一半将在每个细胞周期中生成突变。总体而言，血液细胞中16%的突变归因于SBS19，而类似比例的血液癌症驱动突变也表现出这一标志。这些数据表明，存在一类DNA损伤，它们来源于内源性和外源性致突变物，每个基因组中数量较少，能够持续数月至数年，并且可能在体细胞的突变负担中占据相当大的比例。

据了解，DNA持续受到损伤，使得每个细胞在任何时刻都带有成千上万个单独的DNA损伤。DNA修复的效率意味着大多数已知类型的损伤，具有分钟到小时级的半衰期，但DNA损伤能持续多长时间仍然未知。

附：英文原文

Title: Prolonged persistence of mutagenic DNA lesions in somatic cells

Author: Spencer Chapman, Michael, Mitchell, Emily, Yoshida, Kenichi, Williams, Nicholas, Fabre, Margarete A., Ranzoni, Anna Maria, Robinson, Philip S., Kregar, Lori D., Wilk, Matthias, Boettcher, Steffen, Mahbubani, Krishnaa, Saeb Parsy, Kourosh, Gowers, Kate H. C., Janes, Sam M., Ng, Stanley W. K., Hoare, Matt, Green, Anthony R., Vassiliou, George S., Cvejic, Ana, Manz, Markus G., Laurenti, Elisa, Martincorena, Iigo, Stratton, Michael R., Nangalia, Jyoti, Coorens, Tim H. H., Campbell, Peter J.

Issue&Volume: 2025-01-15

Abstract: DNA is subject to continual damage, leaving each cell with thousands of individual DNA lesions at any given moment1,2,3. The efficiency of DNA repair means that most known classes of lesion have a half-life of minutes to hours3,4, but the extent to which DNA damage can persist for longer durations remains unknown. Here, using high-resolution phylogenetic trees from 89 donors, we identified mutations arising from 818 DNA lesions that persisted across multiple cell cycles in normal human stem cells from blood, liver and bronchial epithelium5,6,7,8,9,10,11,12. Persistent DNA lesions occurred at increased rates, with distinctive mutational signatures, in donors exposed to tobacco or chemotherapy, suggesting that they can arise from exogenous mutagens. In haematopoietic stem cells, persistent DNA lesions, probably from endogenous sources, generated the characteristic mutational signature SBS1913; occurred steadily throughout life, including in utero; and endured for 2.2 years on average, with 15–25% of lesions lasting at least 3 years. We estimate that on average, a haematopoietic stem cell has approximately eight such lesions at any moment in time, half of which will generate a mutation with each cell cycle. Overall, 16% of mutations in blood cells are attributable to SBS19, and similar proportions of driver mutations in blood cancers exhibit this signature. These data indicate the existence of a family of DNA lesions that arise from endogenous and exogenous mutagens, are present in low numbers per genome, persist for months to years, and can generate a substantial fraction of the mutation burden of somatic cells.

DOI: 10.1038/s41586-024-08423-8

Source: https://www.nature.com/articles/s41586-024-08423-8