The linker histone H1–BRCA1 axis is a crucial mediator of replication fork stability

The replication-dependent histones H1 interact with BRCA1 upon replication stress. Cells deficient for H1 fail to recruit BRCA1 to stalled replication forks and undergo fork resection and collapse. The maintenance of genome integrity relies on replication fork stabilization upon encountering endogenous and exogenous sources of DNA damage. How this process is coordinated with the local chromatin environment remains poorly defined. Here, we show that the replication-dependent histone H1 variants interact with the tumour suppressor BRCA1 in a replication stress–dependent manner. Transient loss of the replication-dependent histones H1 does not affect fork progression in unchallenged conditions but leads to the accumulation of stalled replication intermediates. Upon challenge with hydroxyurea, cells deficient for histone H1 variants fail to recruit BRCA1 to stalled replication forks and undergo MRE11-dependent fork resection and collapse, which ultimately leads to genomic instability and cell death. In summary, our work defines an essential role of the replication-dependent histone H1 variants in mediating BRCA1-dependent fork protection and genome stability.

• Publication year

  2023

• Venue

  Life Science Alliance

• Publication date

  2023-06-26

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.26508/lsa.202301933PMID 37364916PMCID 10292663
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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