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.

着丝粒完整性是细胞分裂期间染色体正确分离的关键¹。着丝粒具有独特的染色质特征，这对着丝粒的维持至关重要²。尽管它们本质上是脆弱的并且代表了染色体重排的热点³，但对于如何保留响应 DNA 损伤的着丝粒完整性知之甚少。^{通过同源重组进行的 DNA 修复需要姐妹染色单体的存在，并且在细胞周期4}的 G1 期受到抑制. 在这里，我们证明尽管没有姐妹染色单体，但 G1 期着丝粒处发生的 DNA 断裂会募集同源重组机制。从机制上讲，我们表明着丝粒特异性组蛋白 H3 变体 CENP-A 及其伴侣 HJURP，以及组蛋白 3 (H3K4me2) 中赖氨酸 4 的二甲基化，使一系列事件能够导致 G1 中同源重组的许可。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 末端切除。CENP-A 和 HJURP 与去泛素化酶 USP11 相互作用，从而形成 RAD51–BRCA1–BRCA2 复合物⁵并使着丝粒易于在 G1 期进行 RAD51 募集和同源重组。最后，我们表明抑制 G1 期同源重组会导致着丝粒不稳定和染色体易位。我们的结果支持一个模型，在该模型中，在整个细胞周期中发生着丝粒断裂处的同源重组许可，以防止诱变 DNA 修复途径的激活并保持着丝粒完整性。