小柯机器人

美国霍华德·休斯医学研究所David Pellman团队近日取得一项新成果。他们研究发现病理性DNA碱基切除修复引起的细胞质染色体断裂。该研究成果2022年4月27日在线发表于《自然》杂志上。

在这里，研究人员确定了一种能解释这种DNA损伤得主要机制。微核积累了大量的RNA-DNA杂合体，这些杂合体由ADAR酶（作用于RNA的腺嘌呤脱氨酶）编辑以产生脱氧肌苷(dI)。然后通过DNA碱基切除修复 (BER) 糖基化酶MPG（N-甲基-嘌呤DNA糖基化酶）将dI转化为无碱基位点。这些无碱基位点被BER核酸内切酶APE1（无嘌呤/无嘧啶核酸内切酶）切割，产生单链DNA切口，可通过DNA复制或当相反链上出现紧密间隔的切口时转化为DNA双链断裂。

该模型预测MPG应该能够从RNA-DNA杂合体的DNA链中去除dI碱基，研究人员使用纯蛋白质和寡核苷酸底物证明了这一点。这些发现确定了微核染色体断裂的机制，这是产生染色体碎裂的重要步骤。研究人员认为真核细胞质仅破坏已经存在缺陷的染色体，而不是破坏任何正常的染色体，例如此处描述的DNA碱基异常。

据介绍，染色体碎裂是一种灾难性的突变过程，可促进肿瘤发生并导致先天性疾病。 染色体碎裂起源于称为微核或染色体桥的核畸变。这些结构具有脆弱的核包膜 (NEs)，它们会自发破裂，当染色质暴露于间期细胞质时会导致DNA损伤。

附：英文原文

Title: Breakage of cytoplasmic chromosomes by pathological DNA base excision repair

Author: Tang, Shangming, Stokasimov, Ema, Cui, Yuxiang, Pellman, David

Issue&Volume: 2022-04-27

Abstract: Chromothripsis is a catastrophic mutational process that promotes tumorigenesis and causes congenital disease1–4. Chromothripsis originates from aberrations of nuclei called micronuclei or chromosome bridge5–8. These structures have fragile nuclear envelopes (NEs) that spontaneously rupture9,10, leading to DNA damage when chromatin is exposed to the interphase cytoplasm. Here, we identify a mechanism explaining a major fraction of this DNA damage. Micronuclei accumulate large amounts of RNA-DNA hybrids, which are edited by ADAR enzymes (adenine deaminases acting on RNA) to generate deoxyinosine (dI). dI is then converted into abasic sites by a DNA base excision repair (BER) glycosylase, MPG (N-methyl-purine DNA glycosylase)11,12. These abasic sites are cleaved by the BER endonuclease, APE1 (apurinic/apyrimidinic endonuclease)12, creating single-strand DNA nicks that can be converted to DNA double strand breaks by DNA replication or when closely spaced nicks occur on opposite strands13,14. This model predicts that MPG should be able to remove the dI base from the DNA strand of RNA-DNA hybrids, which we demonstrate using pure proteins and oligonucleotide substrates. These findings identify a mechanism for fragmentation of micronuclear chromosomes, an important step in generating chromothripsis. Rather than breaking any normal chromosome, we propose that the eukaryotic cytoplasm only damages chromosomes with preexisting defects such as the DNA base abnormality described here.

DOI: 10.1038/s41586-022-04767-1

Source: https://www.nature.com/articles/s41586-022-04767-1

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