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CENP-B 可维持因逆转录转座子 LTR 而暂停的复制叉处的基因组完整性。

CENP-B preserves genome integrity at replication forks paused by retrotransposon LTR.

机构信息

Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA.

出版信息

Nature. 2011 Jan 6;469(7328):112-5. doi: 10.1038/nature09608. Epub 2010 Dec 12.

Abstract

Centromere-binding protein B (CENP-B) is a widely conserved DNA binding factor associated with heterochromatin and centromeric satellite repeats. In fission yeast, CENP-B homologues have been shown to silence long terminal repeat (LTR) retrotransposons by recruiting histone deacetylases. However, CENP-B factors also have unexplained roles in DNA replication. Here we show that a molecular function of CENP-B is to promote replication-fork progression through the LTR. Mutants have increased genomic instability caused by replication-fork blockage that depends on the DNA binding factor switch-activating protein 1 (Sap1), which is directly recruited by the LTR. The loss of Sap1-dependent barrier activity allows the unhindered progression of the replication fork, but results in rearrangements deleterious to the retrotransposon. We conclude that retrotransposons influence replication polarity through recruitment of Sap1 and transposition near replication-fork blocks, whereas CENP-B counteracts this activity and promotes fork stability. Our results may account for the role of LTR in fragile sites, and for the association of CENP-B with pericentromeric heterochromatin and tandem satellite repeats.

摘要

着丝粒结合蛋白 B(CENP-B)是一种广泛保守的 DNA 结合因子,与异染色质和着丝粒卫星重复序列相关联。在裂殖酵母中,已经表明 CENP-B 同源物通过招募组蛋白去乙酰化酶来沉默长末端重复(LTR)反转录转座子。然而,CENP-B 因子在 DNA 复制中也有尚未解释的作用。在这里,我们表明 CENP-B 的一个分子功能是通过 LTR 促进复制叉的进展。突变体由于复制叉阻塞而导致基因组不稳定性增加,这依赖于 DNA 结合因子开关激活蛋白 1(Sap1),它直接被 LTR 募集。丧失 Sap1 依赖性屏障活性允许复制叉不受阻碍地前进,但导致对反转录转座子有害的重排。我们得出结论,反转录转座子通过募集 Sap1 并在复制叉阻塞附近转位来影响复制极性,而 CENP-B 则拮抗这种活性并促进叉的稳定性。我们的结果可以解释 LTR 在脆弱部位的作用,以及 CENP-B 与着丝粒周围异染色质和串联卫星重复序列的关联。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9f78/3057531/472c37c76912/nihms247818f1.jpg

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