SummaryComponents of the Fanconi anemia and homologous recombination pathways play a vital role in protecting newly replicated DNA from uncontrolled nucleolytic degradation, safeguarding genome stability. Here we report that histone methylation by the lysine methyltransferase SETD1A is crucial for protecting stalled replication forks from deleterious resection. Depletion of SETD1A sensitizes cells to replication stress and leads to uncontrolled DNA2-dependent resection of damaged replication forks. The ability of SETD1A to prevent degradation of these structures is mediated by its ability to catalyze methylation on Lys4 of histone H3 (H3K4) at replication forks, which enhances FANCD2-dependent histone chaperone activity. Suppressing H3K4 methylation or expression of a chaperone-defective FANCD2 mutant leads to loss of RAD51 nucleofilament stability and severe nucleolytic degradation of replication forks. Our work identifies epigenetic modification and histone mobility as critical regulatory mechanisms in maintaining genome stability by restraining nucleases from irreparably damaging stalled replication forks.

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Background: A study was conducted at the University Hospital of Patras between January 2002 and December 2003 to investigate antibiotic resistance patterns and clonality of Salmonella enterica in southwestern Greece. Methods: Ninety-five isolates recovered from different outpatients were characterized by specific antisera and were tested for their susceptibility to various antimicrobial agents. Clones were identified by pulsed-field gel electrophoresis (PFGE) of XbaI chromosomal DNA digests. Results: Five serotypes were characterized among 95 isolates, recovered mainly from children, with the predominance of Salmonellaenteritidis followed by Salmonellatyphimurium. The strains were further distinguished by PFGE to 16 clones. The majority of S.enteritidis (61 strains) belonged to clone A, already characterized in Greece, while S.typhimurium (18 isolates) belonged to 3 clones, exhibiting multiresistant phenotypes. Conclusions: One clone S.enteritidis, type A, circulates in southwestern Greece, mainly during summer, while clonality was also observed among S.typhimurium.

We recently identified that methylation of lysine 4 of histone H3 (H3K4) by SETD1A (SET domain containing 1A) maintains genome stability by protecting newly-replicated DNA from degradation. Mechanistically, SETD1A-dependent histone methylation regulates nucleosome mobilisation by FANCD2 (FA complementation group D2), a crucial step in maintaining genome integrity with important implications in chemo-sensitivity.

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