A role for the Saccharomyces cerevisiae Rtt109 histone acetyltransferase in R-loop homeostasis and associated genome instability

• Published in: Genetics (Austin) 2022-08, Vol.222 (1)
• Main Authors: Cañas, Juan Carlos, García-Rubio, María Luisa, García, Alicia, Antequera, Francisco, Gómez-González, Belén, Aguilera, Andrés
• Format: Article
• Language: English
• Subjects: Acetylation; Chromatin; Complexity; Context; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA damage; DNA repair; Genetics; Genomes; Genomic instability; Histone acetyltransferase; Histone H3; Histones; Homeostasis; Hybridization; Hybrids; Investigation; Metabolism; R-loops; Repair; Replication; Replication forks; Ribonucleic acid; RNA; Saccharomyces cerevisiae; Stability; Stalling; Yeast; Yeasts
• ISSN: 1943-2631; 0016-6731; 1943-2631
• DOI: 10.1093/genetics/iyac108

Abstract The stability of the genome is occasionally challenged by the formation of DNA–RNA hybrids and R-loops, which can be influenced by the chromatin context. This is mainly due to the fact that DNA–RNA hybrids hamper the progression of replication forks, leading to fork stalling and, ultimately, DNA breaks. Through a specific screening of chromatin modifiers performed in the yeast Saccharomyces cerevisiae, we have found that the Rtt109 histone acetyltransferase is involved in several steps of R-loop-metabolism and their associated genetic instability. On the one hand, Rtt109 prevents DNA–RNA hybridization by the acetylation of histone H3 lysines 14 and 23 and, on the other hand, it is involved in the repair of replication-born DNA breaks, such as those that can be caused by R-loops, by acetylating lysines 14 and 56. In addition, Rtt109 loss renders cells highly sensitive to replication stress in combination with R-loop-accumulating THO-complex mutants. Our data evidence that the chromatin context simultaneously influences the occurrence of DNA–RNA hybrid-associated DNA damage and its repair, adding complexity to the source of R-loop-associated genetic instability. Genome stability is threatened by DNA-RNA hybrids and R loops. Cañas et al. find the Rtt109 histone acetyltransferase prevents DNA-RNA hybridization by targeting histone H3 lysines 14 and 23. By acetylating lysines 14 and 56, Rtt109 functions in the repair of replication-born DNA breaks, such as those ultimately caused by R-loops. These findings reveal a key role of chromatin in both the occurrence of spontaneous DNA damage and its repair, adding complexity to R loop-associated genetic instability.