Precise control of transcription condensates across S phase balances linker histone expression with DNA replication, ensuring genome stability

Transcription condensates are liquid-like compartments where transcription factors, co-activators, and RNA polymerases are selectively enriched and regulate transcription initiation of associated genes. While the principles governing the enrichment of proteins within transcription condensates are being elucidated, mechanisms that coordinate condensate dynamics with Other nuclear processes, such as DNA replication, have not been identified. We show in human cells that at the G1/S cell-cycle transition, large transcription condensates form at histone locus bodies (HLBs) in a cyclin-dependent kinase 1 and 2 (CDK1/2)-dependent manner. By mid-S phase, ataxia-telangiectasia and Rad3-related kinase (ATR) accumulates within HLBs and dissolves the associated condensates via its downstream effector, Chk1. Failure to dissolve condensates results in overexpression of linker H1 histones and nucleus-wide DNA damage. Moreover, an imbalance in the different linker histones accentuates DNA damage in ATR-CHK1-deficient cells. Our work reveals how transcription condensates are precisely controlled in the S phase to fine-tune gene activation and safeguard genome stability.

ATR; DNA damage; MED1; genome stability; histone locus body; linker histones; transcription condensates.