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DNA复制时间直接调控致癌性染色体易位的频率
作者:小柯机器人 发布时间:2022/9/18 20:52:25

奥地利分子病理学研究所Rushad Pavri团队发现,DNA复制时间直接调控致癌性染色体易位的频率。2022年9月16日,国际知名学术期刊《科学》发表了这一成果。

研究人员发现,在B细胞的抗体成熟过程中,DNA复制时机(RT)直接调控淋巴瘤Myc易位,这是在DNA双链断裂(DSB)的下游,而且与DSB频率无关。微小染色体维持复合物的耗竭改变了复制原点的活性,减少了易位,并解除了对全局RT的调节。破坏Myc的单一起源会导致RT从早期到晚期的转换,失去易位,并减少与免疫球蛋白重链(Igh)基因的接近,它的主要易位伙伴。这些表型通过恢复早期RT而被逆转。早期RT的中断也减少了人类白血病细胞的致瘤易位。因此,RT构成了易位生物发生的一般机制,将DSB的形成与DSB连接联系起来。

据介绍,染色体易位是由DSB的连接导致的,并经常导致癌症。然而,连接DSB形成和DSB连接的步骤仍未被破译。

附:英文原文

Title: DNA replication timing directly regulates the frequency of oncogenic chromosomal translocations

Author: Mihaela Peycheva, Tobias Neumann, Daniel Malzl, Mariia Nazarova, Ursula E. Schoeberl, Rushad Pavri

Issue&Volume: 2022-09-16

Abstract: Chromosomal translocations result from the joining of DNA double-strand breaks (DSBs) and frequently cause cancer. However, the steps linking DSB formation to DSB ligation remain undeciphered. We report that DNA replication timing (RT) directly regulates lymphomagenic Myc translocations during antibody maturation in B cells downstream of DSBs and independently of DSB frequency. Depletion of minichromosome maintenance complexes alters replication origin activity, decreases translocations, and deregulates global RT. Ablating a single origin at Myc causes an early-to-late RT switch, loss of translocations, and reduced proximity with the immunoglobulin heavy chain (Igh) gene, its major translocation partner. These phenotypes were reversed by restoring early RT. Disruption of early RT also reduced tumorigenic translocations in human leukemic cells. Thus, RT constitutes a general mechanism in translocation biogenesis linking DSB formation to DSB ligation.

DOI: abj5502

Source: https://www.science.org/doi/10.1126/science.abj5502

 

期刊信息
Science:《科学》,创刊于1880年。隶属于美国科学促进会,最新IF:41.037