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DNA聚合酶的缺陷导致正常人类细胞中的体细胞突变负担增加
2021-10-09 14:23

英国威康桑格研究所Michael R. Stratton、爱丁堡大学Ian Tomlinson等研究人员合作发现,DNA聚合酶的缺陷导致正常人类细胞中的体细胞突变负担增加。该项研究成果于2021年9月30日在线发表在《自然—遗传学》杂志上。

研究人员对具有生殖系POLE/POLD1突变个体的正常组织和肿瘤DNA进行了测序。在正常成人体细胞类型、早期胚胎发育过程中和精子中,研究人员发现了具有特征性突变特征的突变负担增加。因此,人类生理可以容忍普遍升高的突变负担。除了癌症风险增加外,具有生殖系POLE/POLD1突变的个体并没有表现出明显的早衰特征。这些结果并不支持这样一种模式,即所有的衰老特征都归因于生命中积累的体细胞突变负担直接导致的广泛细胞功能失调。

据介绍,体细胞中的突变积累有助于癌症的发展,并被认为是衰老的一个原因。DNA聚合酶Pol ε和Pol δ在细胞分裂期间复制DNA。然而,在一些癌症中,由于获得性POLE/POLD1外切酶域突变而导致的校对缺陷,使体细胞突变负担明显增加,并具有独特的突变特征。胚胎POLE/POLD1突变导致家族性癌症倾向。

附:英文原文

Title: Increased somatic mutation burdens in normal human cells due to defective DNA polymerases

Author: Robinson, Philip S., Coorens, Tim H. H., Palles, Claire, Mitchell, Emily, Abascal, Federico, Olafsson, Sigurgeir, Lee, Bernard C. H., Lawson, Andrew R. J., Lee-Six, Henry, Moore, Luiza, Sanders, Mathijs A., Hewinson, James, Martin, Lynn, Pinna, Claudia M. A., Galavotti, Sara, Rahbari, Raheleh, Campbell, Peter J., Martincorena, Iigo, Tomlinson, Ian, Stratton, Michael R.

Issue&Volume: 2021-09-30

Abstract: Mutation accumulation in somatic cells contributes to cancer development and is proposed as a cause of aging. DNA polymerases Polε and Polδ replicate DNA during cell division. However, in some cancers, defective proofreading due to acquired POLE/POLD1 exonuclease domain mutations causes markedly elevated somatic mutation burdens with distinctive mutational signatures. Germline POLE/POLD1 mutations cause familial cancer predisposition. Here, we sequenced normal tissue and tumor DNA from individuals with germline POLE/POLD1 mutations. Increased mutation burdens with characteristic mutational signatures were found in normal adult somatic cell types, during early embryogenesis and in sperm. Thus human physiology can tolerate ubiquitously elevated mutation burdens. Except for increased cancer risk, individuals with germline POLE/POLD1 mutations do not exhibit overt features of premature aging. These results do not support a model in which all features of aging are attributable to widespread cell malfunction directly resulting from somatic mutation burdens accrued during life.

DOI: 10.1038/s41588-021-00930-y

Source: https://www.nature.com/articles/s41588-021-00930-y

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:41.307
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex


本期文章:《自然—遗传学》:Online/在线发表

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