The 7SK small nuclear ribonucleoprotein links the cell responses to transcription and replication stress by promoting replication fork reversal and homologous recombination

Abstract

The 7SK small nuclear ribonucleoprotein (7SK-snRNP) releases positive transcription elongation factor b to sustain RNA polymerase II (RNAPII) activity during transcription stress. Many conditions that block transcription also cause replication stress, and 7SK-snRNP components have potential roles in transcription–replication conflicts and double-strand break (DSB) repair. Here, we investigate roles of 7SK-snRNP components in replication stress responses. We report that 7SK-snRNP promotes replication fork slowing in response to agents that cause both replication and transcription stress. Our data suggest that 7SK-snRNP facilitates RAD51-mediated replication fork reversal rather than transcription–replication conflicts. 7SK-snRNP also promotes RAD51 recruitment to replication-associated DSBs or post-replicative gaps under conditions of transcription stress and supports homologous recombination at direct DSBs. In contrast, 7SK-snRNP components are not required for RAD51 recruitment in response to hydroxyurea. Our data support that LARP7 functions during replication stress independently of its interaction with BRCA1, and that LARP7 and HEXIM1 promote survival of replication stress. 7SK-snRNP components are not recruited to stressed replication forks, and RNAPII inhibition phenocopies loss of these proteins. Our data support a model where 7SK-snRNP modulation of RNAPII activity helps facilitate several RAD51 functions under transcription stress conditions, thereby connecting the cell responses to transcription and replication stress.