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Nature:揭示染色体重排路径或为开发抑制癌症的疗法提供思路

来源:生物谷 2013-09-09 23:19

2013年9月9日 讯 /生物谷BIOON/ --近日,刊登在国际著名杂志Nature上的一篇研究报告中,来自德克萨斯大学健康科学中心的研究者通过研究揭示了哺乳动物细胞中染色体重排的两种途径,其改变或和某些癌症以及遗传性障碍直接相关。

研究者Edward P. (Paul) Hasty博士表示,这项研究为我们靶向抑制染色体重排开发抑制癌症的疗法提供了新的思路,这两种重排是通过DNA重复的重新组合来完成的,而且重排路径对于DNA的合成也非常重要;因此研究者推测,染色体的重排是随着DNA的合成而同时进行的。

文章中研究者使用培养液中培养的小鼠胚胎干细胞来进行试验,研究小组测定了正常细胞中DNA重复发生重组的发生率,也就是所谓的“重复融合(repeat fusion)”,随后研究者观察了受遗传突变影响的细胞中DNA重复融合的发生率。

在细胞分裂期间,DNA可以卷曲成双链结构形成染色体,人类细胞一般都含有22对常染色体,以及一对性染色体,后者决定了个体的性别;女性含有一对X染色体,而男性则分别具有X和Y染色体。最后研究者表示,我们希望我们的研究发现可以帮助科学家更好地理解引发染色体不稳定的分子机制,这就为理解某些癌症的发生以及开发相应的疗法提供了希望和帮助。(生物谷Bioon.com)

Two replication fork maintenance pathways fuse inverted repeats to rearrange chromosomes

Lingchuan Hu, Tae Moon Kim, Mi Young Son, Sung-A Kim, Cory L. Holland, Satoshi Tateishi, Dong Hyun Kim, P. Renee Yew, Cristina Montagna, Lavinia C. Dumitrache & Paul Hasty

Replication fork maintenance pathways preserve chromosomes, but their faulty application at nonallelic repeats could generate rearrangements causing cancer, genomic disorders and speciation1, 2, 3. Potential causal mechanisms are homologous recombination and error-free postreplication repair (EF-PRR). Homologous recombination repairs damage-induced DNA double-strand breaks (DSBs) and single-ended DSBs within replication. To facilitate homologous recombination, the recombinase RAD51 and mediator BRCA2 form a filament on the 3′ DNA strand at a break to enable annealing to the complementary sister chromatid4 while the RecQ helicase, BLM (Bloom syndrome mutated) suppresses crossing over to prevent recombination5. Homologous recombination also stabilizes6, 7 and restarts8, 9 replication forks without a DSB10, 11. EF-PRR bypasses DNA incongruities that impede replication by ubiquitinating PCNA (proliferating cell nuclear antigen) using the RAD6–RAD18 and UBC13–MMS2–RAD5 ubiquitin ligase complexes12. Some components are common to both homologous recombination and EF-PRR such as RAD51 and RAD1813, 14. Here we delineate two pathways that spontaneously fuse inverted repeats to generate unstable chromosomal rearrangements in wild-type mouse embryonic stem (ES) cells. Gamma-radiation induced a BLM-regulated pathway that selectively fused identical, but not mismatched, repeats. By contrast, ultraviolet light induced a RAD18-dependent pathway that efficiently fused mismatched repeats. Furthermore, TREX2 (a 3′5′ exonuclease) suppressed identical repeat fusion but enhanced mismatched repeat fusion, clearly separating these pathways. TREX2 associated with UBC13 and enhanced PCNA ubiquitination in response to ultraviolet light, consistent with it being a novel member of EF-PRR. RAD18 and TREX2 also suppressed replication fork stalling in response to nucleotide depletion. Interestingly, replication fork stalling induced fusion for identical and mismatched repeats, implicating faulty replication as a causal mechanism for both pathways.

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