Figure 3. Loss of Bre1 (RNF20/40) increases chromosomal instability (CIN), which explains increased cell death and acquisition of the malignant phenotype. Bre1 depletion impairs homologous recombination and the processing of canonical histone mRNAs, both of which act to protect genomic stability during replication. Incorrect processing of replication-dependent histone mRNA 3′-ends, as well as suboptimal transcription of genes in heterochromatin that has become de-silenced as a result of Bre1 deficiency, create conditions that favor co-transcriptional formation of R-loops, blocking replication forks.