![]() ![]() Set1C was initially shown to be involved in DSB repair by NHEJ 32 recent data indicate that Set1-dependent H3K4 methylation acts as a decelerator for replisome progression at highly transcribed genes to prevent Transcription-Replication conflicts (TRC) 33 and limits DNA damage in response to changes in S-phase dynamics 34. ![]() While the absence of Set1 affects all states of H3K4 methylation, inactivation of Spp1, the PHD finger domain-containing subunit, affects only H3K4me3 30, 31. The Set1 subunit of Set1C acts as a scaffold for seven additional subunits (Swd1, Swd2, Swd3, Bre2, Sdc1, Shg1, and Spp1) 27, 28, 29, 30. ![]() In budding yeast, all patterns of H3K4 methylation (mono-, di-, and tri-) are deposited by Set1 histone methyltransferase, which belongs to an evolutionarily conserved complex (called Set1C or COMPASS). While chromatin remodelers such as INO80, SWI/SNF, Fun30, and RSC were shown to remodel the chromatin surrounding a double-strand break (DSB) to allow resection 21, 22, 23, 24, 25, how replication stress responses and repair mechanisms are shaped by the chromatin environment is still to be fully understood 26. The nascent chromatin contains a mix of recycled parental histones (marked by H3K4me3) and newly synthesized histones (marked by H3K56ac) 19, 20. Histone remodelers and chaperones aid the replisome in nucleosome disassembly ahead of the fork and reassembly behind the fork 18. The stabilized fork can then be rescued by downstream forks or by recombination 9, 11, 14.ĭNA replication occurs in a crowded chromatin environment where the replisome itself can disrupt chromatin organization 15, 16, 17. A key component to nascent DNA protection is RPA-coated ssDNA that can be displaced by Rad52 and allow Rad51 RAD51 loading to the nascent DNA 13, 14. ![]() Stalled replication forks can be processed by resection nucleases such as Exo1 EXO1/Dna2 DNA2/Mre11 MRE11 and remodelers such as MRX MRN, Mph1 FANCM/Rad5, RAD51 while protecting the nascent DNA strands to allow fork recovery 11, 12. The regulation of the choice of repair processes is still to be fully understood 2, 8, 10, 11, 12. Several fork-associated repair mechanisms promote fork recovery by bypassing obstacles such as translesion synthesis and re-priming activities, template switch, break-induced replication and homologous recombination 7, 8, 9, 10. Cells have adapted to cope with such challenges through the collaborative work between replisome components, fork repair machinery and cell cycle-dependent kinases, ensuring proper replication resumption 7. These challenges, if not regulated, can lead to DNA breaks driving genomic instability and cancer development 4, 5, 6. For instance, the replisome could stall and collapse when colliding with transcriptional machinery or facing a Replication Fork Barrier (RFB) such as protein bound-DNA or repetitive sequences 3. Alteration of replication fork (RF) progression, defined generally as replication stress, is caused by numerous mechanisms 2. We propose that Spp1 limits the remodeling of the fork, which ultimately limits nascent DNA availability to nucleases.ĭuring DNA replication, the replisome must unwind the DNA double helix, ensure faithful DNA duplication as well as deal with any impediment it may encounter 1. Finally, we report that Spp1 protects nascent DNA at the Tus/ Ter stalled replication fork. We further show that deleting SPP 1 increases the mutation rate upstream of the barrier favoring the accumulation of microdeletions. Its recruitment prevents the accumulation of ssDNA at the stalled fork by restricting the access of Exo1. Spp1 chromatin recruitment depends on the interaction of its PHD domain with H3K4me3 parental histones deposited behind the stalled fork. We report that the Set1C subunit Spp1 is recruited behind the stalled replication fork independently of its interaction with Set1. Here, we used the bacterial Tus/ Ter barrier known to induce a site-specific replication fork stalling in S. Homologous recombination factors play a crucial role in protecting nascent DNA during DNA replication, but the role of chromatin in this process is largely unknown. ![]()
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