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DNA 复制的干扰可导致与双链断裂无关的有丝分裂染色体断裂。

Interference in DNA replication can cause mitotic chromosomal breakage unassociated with double-strand breaks.

机构信息

Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshidakonoe, Sakyo-ku, Kyoto, Japan.

出版信息

PLoS One. 2013;8(4):e60043. doi: 10.1371/journal.pone.0060043. Epub 2013 Apr 3.

DOI:10.1371/journal.pone.0060043
PMID:23573231
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3616066/
Abstract

Morphological analysis of mitotic chromosomes is used to detect mutagenic chemical compounds and to estimate the dose of ionizing radiation to be administered. It has long been believed that chromosomal breaks are always associated with double-strand breaks (DSBs). We here provide compelling evidence against this canonical theory. We employed a genetic approach using two cell lines, chicken DT40 and human Nalm-6. We measured the number of chromosomal breaks induced by three replication-blocking agents (aphidicolin, 5-fluorouracil, and hydroxyurea) in DSB-repair-proficient wild-type cells and cells deficient in both homologous recombination and nonhomologous end-joining (the two major DSB-repair pathways). Exposure of cells to the three replication-blocking agents for at least two cell cycles resulted in comparable numbers of chromosomal breaks for RAD54(-/-/)KU70(-/-) DT40 clones and wild-type cells. Likewise, the numbers of chromosomal breaks induced in RAD54(-/-/)LIG4(-/-) Nalm-6 clones and wild-type cells were also comparable. These data indicate that the replication-blocking agents can cause chromosomal breaks unassociated with DSBs. In contrast with DSB-repair-deficient cells, chicken DT40 cells deficient in PIF1 or ATRIP, which molecules contribute to the completion of DNA replication, displayed higher numbers of mitotic chromosomal breaks induced by aphidicolin than did wild-type cells, suggesting that single-strand gaps left unreplicated may result in mitotic chromosomal breaks.

摘要

有丝分裂染色体的形态分析用于检测诱变化学化合物，并估计要施用的电离辐射剂量。长期以来，人们一直认为染色体断裂总是与双链断裂（DSB）相关。我们在这里提供了令人信服的证据来反驳这个经典理论。我们使用两种细胞系，鸡 DT40 和人 Nalm-6，采用遗传方法进行研究。我们测量了三种复制阻断剂（阿非迪霉素、5-氟尿嘧啶和羟基脲）在 DSB 修复功能正常的野生型细胞和同源重组和非同源末端连接（两种主要的 DSB 修复途径）均缺陷的细胞中诱导的染色体断裂数。细胞暴露于三种复制阻断剂中至少两个细胞周期，RAD54(-/-)/KU70(-/-) DT40 克隆和野生型细胞的染色体断裂数相当。同样，RAD54(-/-)/LIG4(-/-) Nalm-6 克隆和野生型细胞中诱导的染色体断裂数也相当。这些数据表明，复制阻断剂可以引起与 DSB 无关的染色体断裂。与 DSB 修复缺陷细胞相反，鸡 DT40 细胞中缺乏参与 DNA 复制完成的 PIF1 或 ATRIP，这些分子显示出比野生型细胞更高的阿非迪霉素诱导的有丝分裂染色体断裂数，表明未复制的单链缺口可能导致有丝分裂染色体断裂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/264a/3616066/83a5a62593a9/pone.0060043.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/264a/3616066/19ebfd9bb721/pone.0060043.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/264a/3616066/6454b51f2b08/pone.0060043.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/264a/3616066/39ea1e13e2de/pone.0060043.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/264a/3616066/64d0962e2527/pone.0060043.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/264a/3616066/83a5a62593a9/pone.0060043.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/264a/3616066/19ebfd9bb721/pone.0060043.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/264a/3616066/6454b51f2b08/pone.0060043.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/264a/3616066/39ea1e13e2de/pone.0060043.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/264a/3616066/64d0962e2527/pone.0060043.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/264a/3616066/83a5a62593a9/pone.0060043.g005.jpg

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