'Mitotic drive' of expanded CTG repeats in myotonic dystrophy type 1 (DM1)
'Mitotic drive' of expanded CTG repeats in myotonic dystrophy type 1 (DM1)
复制标题
DOI：
10.1093/hmg/10.8.855
复制
发表时间：
2001-04-01
影响因子：
3.5
通讯作者：
Ashizawa, T
中科院分区：
文献类型：
--
作者：
Khajavi, M;Tari, AM;Ashizawa, T
在强直性肌营养不良1型(DM1)中，扩增的CTG重复序列在体细胞和生殖系组织中显示重复大小不稳定，并倾向于进一步扩张。为了探讨这种扩增偏向的机制，从18例DM1患者和6名正常人的血细胞中克隆了29个DM1和6个正常淋巴母细胞系(LBCL)。在所有29个细胞系中，扩大的CTG重复等位基因通过“逐步”突变逐渐向进一步扩大转移。在这29个细胞系中，有8个产生了一个快速增殖的突变体，获得了较大的重复长度，成为主要的等位基因群体，最终取代了祖代等位基因群体。通过混合不同重复扩增的细胞系，我们发现在培养中CTG重复扩增较大的细胞比扩增较小的细胞具有生长优势。这种生长优势归因于由Erk1，2激活介导的细胞增殖增加，而Erk1，2激活受p21(WAF1)的负调控。这种现象，我们称之为有丝分裂驱动，是一种新的机制，可以在组织水平上解释DM1 CTG重复序列不稳定的扩展偏向，而不依赖于基于DNA的扩展模型。DM1LBCL细胞的寿命明显短于正常细胞系。因此，我们提出了一种假设，DM1 LBCL通过与加速增殖相关的过程来驱动自己灭绝。
In myotonic dystrophy type 1 (DM1), an expanded CTG repeat shows repeat size instability in somatic and germ line tissues with a strong bias toward further expansion. To investigate the mechanism of this expansion bias, 29 DM1 and six normal lymphoblastoid cell lines (LBCLs) were single-cell cloned from blood cells of 18 DM1 patients and six normal subjects. In all 29 cell lines, the expanded CTG repeat alleles gradually shifted toward further expansion by 'step-wise' mutations. Of these 29 cell lines, eight yielded a rapidly proliferating mutant with a gain of large repeat size that became the major allele population, eventually replacing the progenitor allele population. By mixing cell lines with different repeat expansions, we found that cells with larger CTG repeat expansion had a growth advantage over those with smaller expansions in culture. This growth advantage was attributable to increased cell proliferation mediated by Erk1,2 activation, which is negatively regulated by p21(WAF1). This phenomenon, which we designated 'mitotic drive', is a novel mechanism which can explain the expansion bias of DM1 CTG repeat instability at the tissue level, on a basis independent of the DNA-based expansion models. The lifespans of the DM1 LBCLs were significantly shorter than normal cell lines. Thus, we propose a hypothesis that DM1 LBCLs drive themselves to extinction through a process related to increased proliferation.