Activation of homologous recombination in G1 preserves centromeric integrity

Duygu Yilmaz, Audrey Furst, Karen Meaburn, Aleksandra Lezaja, Yanlin Wen, Matthias Altmeyer, Bernardo Reina-San-Martin and Evi Soutoglou ()
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Duygu Yilmaz: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Audrey Furst: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Karen Meaburn: Sussex University, School of Life Sciences, University of Sussex
Aleksandra Lezaja: University of Zurich
Yanlin Wen: University of Zurich
Matthias Altmeyer: University of Zurich
Bernardo Reina-San-Martin: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Evi Soutoglou: Institut de Génétique et de Biologie Moléculaire et Cellulaire

Nature, 2021, vol. 600, issue 7890, 748-753

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-04200-z

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