Rpd3L regulates Transcription-Replication Conflict via H3K4 Methylation-Dependent and Independent Chromatin Mechanisms

Disruption of this coordination causes transcription-replication conflicts (TRCs), leading to replication stress and genome instability. How chromatin regulators modulate these processes remains unclear.

Here, we show that the Rpd3L histone deacetylase complex dynamically modulates chromatin state to control replication fork progression and buffer TRCs in Saccharomyces cerevisiae. Rpd3L is targeted through both histone H3 lysine 4 methylation-dependent recruitment and methylation-independent mechanisms engaged under replication stress. Loss of H3K4 methylation or Rpd3L function promotes histone acetylation, accelerates fork progression through transcribed regions, and increases transcription-associated genome instability.