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Eukaryotic genomes are regulated by epigenetic marks that act to modulate transcriptional control as well as to regulate DNA replication and repair. In Arabidopsis thaliana, mutation of the ATXR5 and ATXR6 histone methyltransferases causes reduction in histone H3 lysine 27 monomethylation, transcriptional upregulation of transposons, and a genome instability defect in which there is an accumulation of excess DNA corresponding to pericentromeric heterochromatin. We designed a forward genetic screen to identify suppressors of the atxr5/6 phenotype that uncovered loss-of-function mutations in two components of the TREX-2 complex (AtTHP1, AtSAC3B), a SUMO-interacting E3 ubiquitin ligase (AtSTUbL2) and a methyl-binding domain protein (AtMBD9). Additionally, using a reverse genetic approach, we show that a mutation in a plant homolog of the tumor suppressor gene BRCA1 enhances the atxr5/6 phenotype. Through characterization of these mutations, our results suggest models for the production atxr5 atxr6-induced extra DNA involving conflicts between the replicative and transcriptional processes in the cell, and suggest that the atxr5 atxr6 transcriptional defects may be the cause of the genome instability defects in the mutants. These findings highlight the critical intersection of transcriptional silencing and DNA replication in the maintenance of genome stability of heterochromatin., Author Summary In eukaryotic genomes cellular processes such as transcription and replication need to be tightly controlled in order to promote genomic stability and prevent deleterious mutations. In Arabidopsis thaliana, two redundant histone methyltransferases, ATXR5 and ATXR6, are responsible for the deposition of a silencing epigenetic mark, histone H3 lysine 27 monomethylation. Loss of ATXR5/6 results in transcriptional activation of transposable elements (TEs), upregulation of DNA damage response genes and a genomic instability defect characterized as an excess of DNA corresponding to heterochromatin regions. Using a genetic screen, we sought to find suppressors of the atxr5/6 phenotype, and interestingly, we identified multiple genes implicated in general transcriptional activity. Through genomic characterization of the mutants our data suggest a model where transcriptional silencing of heterochromatin during S-phase is required for proper replication and maintenance of genome stability. These findings emphasize the important relationship between chromatin, transcriptional control and replication in the maintenance of genome stability in a eukaryotic system and identify new players involved in these processes.