小柯机器人

英国萨塞克斯大学 Evi Soutoglou 研究团队研究发现，细胞可以通过激活 G1 期的同源重组修复途径来维持着丝粒的完整性。这一研究成果于2021年12月1日在线发表在《自然》杂志上。

研究团队发现在G1细胞中，尽管没有姐妹染色单体的存在，着丝粒上的 DNA 断裂损伤也能够通过同源重组的方式进行修复。着丝粒特异性组蛋白 H3 的变体 CENP-A，CENP-A 的分子伴侣 HJURP，以及组蛋白H3中第四位赖氨酸的二甲基化修饰 (H3K4me2) 能协同作用，帮助着丝粒在 G1 期细胞中完成同源重组的修复过程。H3K4me2 通过允许DNA损伤诱导的着丝粒转录和增加DNA-RNA杂合体的形成来促进DNA末端的切除。CENP-A 和 HJURP 与去泛素化酶 USP11 相互作用，帮助促进 RAD51-BRCA1-BRCA2 复合物的形成，并在 G1 期帮助着丝粒招募重组蛋白 RAD51 来完成同源物重组修复过程。

最后，研究人员发现，在G1期细胞中抑制同源重组修复会导致着丝粒不稳定和染色体易位。他们的结果支持了这样的模型，着丝粒断裂引发的同源重组修复在整个细胞周期中都能够发生，因此抑制了可能会导致DNA突变的其它损伤修复途径激活，从而维持着丝粒的完整性。

据介绍，着丝粒的完整性是细胞分裂过程中染色体能够正确分离的关键。着丝粒具有独特的染色质特征，这对于着丝粒功能的维持至关重要。尽管着丝粒本身很脆弱，并且是染色体重排的热点区域，但在DNA损伤中如何维持着丝粒的完整性，目前还不清楚。DNA 的同源重组修复在细胞周期的 G1 期受到抑制，因为需要姐妹染色单体的存在。

附：英文原文

Title: Activation of homologous recombination in G1 preserves centromeric integrity

Author: Yilmaz, Duygu, Furst, Audrey, Meaburn, Karen, Lezaja, Aleksandra, Wen, Yanlin, Altmeyer, Matthias, Reina-San-Martin, Bernardo, Soutoglou, Evi

Issue&Volume: 2021-12-01

Abstract: Centromeric integrity is key for proper chromosome segregation during cell division1. Centromeres have unique chromatin features that are essential for centromere maintenance2. Although they are intrinsically fragile and represent hotspots for chromosomal rearrangements3, little is known about how centromere integrity in response to DNA damage is preserved. DNA repair by homologous recombination requires the presence of the sister chromatid and is suppressed in the G1 phase of the cell cycle4. Here we demonstrate that DNA breaks that occur at centromeres in G1 recruit the homologous recombination machinery, despite the absence of a sister chromatid. Mechanistically, we show that the centromere-specific histone H3 variant CENP-A and its chaperone HJURP, together with dimethylation of lysine 4 in histone 3 (H3K4me2), enable a succession of events leading to the licensing of homologous recombination in G1. H3K4me2 promotes DNA-end resection by allowing DNA damage-induced centromeric transcription and increased formation of DNA–RNA hybrids. CENP-A and HJURP interact with the deubiquitinase USP11, enabling formation of the RAD51–BRCA1–BRCA2 complex5 and rendering the centromeres accessible to RAD51 recruitment and homologous recombination in G1. Finally, we show that inhibition of homologous recombination in G1 leads to centromeric instability and chromosomal translocations. Our results support a model in which licensing of homologous recombination at centromeric breaks occurs throughout the cell cycle to prevent the activation of mutagenic DNA repair pathways and preserve centromeric integrity.

DOI: 10.1038/s41586-021-04200-z

Source: https://www.nature.com/articles/s41586-021-04200-z

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