The increased chromatin levels and phosphorylation of RPA upon loss of histone H1 also suggested the premature collapse of replication forks. crucial for life in eukaryotes. Importantly, DNA damage caused by endogenous and external sources threatens the activity and processivity of the replication machinery and requires dedicated pathways for DNA repair (Cortez, 2019). For instance, persistent replication fork stalling, or replication stress, can be induced by non-canonical DNA structures (e.g., G-quadruplexes, G4s), reactive oxygen species, and other by-products of metabolic processes, as well as replicationCtranscription conflicts and oncogene activation in the early stages of tumorigenesis (Zeman & Cimprich, 2014). Consistently, replication stress is considered a major hallmark of malignancy and is currently being exploited for therapeutic purposes (Macheret & Halazonetis, 2015). An important mechanism required for genome stability is the protection of stressed replication forks by fork reversal and nascent strand protection, a process mediated by the concerted action of the RAD51 recombinase and the BRCA1-BRCA2 tumour suppressor pathway, in addition to a series of fork remodellers and processing enzymes (Quinet et al, 2017). How this process takes place in specific genomic regions and chromatin contexts remains Loganic acid poorly defined. Gene expression programmes and cell identity require the regulated control of chromatin Loganic acid structure and epigenetic modifications. Thus, the histone core proteins H2A, H2B, H3, and H4 form an octameric complex that wraps 146 bp of DNA into the nucleosome, the structural and functional unit of chromatin (Zhou et al, 2019). In addition, a chromatin architectural protein, the linker histone H1, binds to extra-nucleosomal DNA and the nucleosome particle to stabilize its folding into higher order chromatin structures, which are essential for regulation of genome function (Kowalski & Pa?yga, 2016). Linker histones H1 are composed of a conserved central globular domain name and two flexible, less conserved, N- and C-terminal tails. Seven histone H1 subtypes have been recognized in somatic cells; of these variants, histones H1.1, H1.2, H1.3, H1.4, and H1.5 are synthesized during the S phase of the cell cycle and are known as replication-dependent variants (Kowalski & Pa?yga, 2016). Although individual histone H1 subtypes present with different DNA affinity and chromatin distribution, their nonredundant functions in regulating PLA2G10 epigenome function remain still debated (Prendergast & Reinberg, 2021). In mice, single or double H1 variant knock-out has no apparent phenotype because of the compensatory up-regulation of other subtypes (Fan et al, 2001). However, a combined lack of H1.2, H1.3, and H1.4 prospects to overall reduction of histone H1 and aberrant differentiation, and results in embryonic lethality, pointing to a fundamental role of the replication-dependent histones H1 in modulating genome structure and function (Fan et al, 2003). Despite this, more recent work has challenged this knowledge and suggests different functions of histone H1 variants in regulating gene expression in specific chromatin and cellular contexts (Prendergast & Reinberg, 2021). Although nucleosome dynamics and post-translational modifications are known to have a fundamental role in the DNA damage response (DDR) and DNA repair, the role of the histone H1 variants in the maintenance of genome stability remains poorly defined. Thorslund et al previously recognized a role of histone H1 in mediating a ubiquitylation cascade at sites of DNA double-strand breaks (DSBs) required for their repair (Thorslund et al, 2015). The role of specific histone H1 variants in this process remains unknown. More recently, Loganic acid a specific role of the histone H1.2 variant has been described in modulating ATM signalling and DNA repair (Li et al, 2018). Here, we show that this replication-dependent histone H1 variants are not required for normal replication fork progression under unchallenged conditions but are necessary for replication fork stability upon fork stalling and replication stress in a BRCA1-dependent manner..