bims-replis Biomed News
on Replisome
Issue of 2025–06–22
two papers selected by
Anna Zawada, International Centre for Translational Eye Research
  1. Specific origin selection and excess functional MCM2-7 loading in ORC-deficient cells.
  2. USP37 prevents premature disassembly of stressed replisomes by TRAIP.
  1. Nucleic Acids Res. 2025 Jun 06. pii: gkaf518. [Epub ahead of print]53(11):
    Specific origin selection and excess functional MCM2-7 loading in ORC-deficient cells.
    Yoshiyuki Shibata, Mihaela Peycheva, Etsuko Shibata, Daniel Malzl, Rushad Pavri, Anindya Dutta.
      The six-subunit origin recognition complex (ORC) loads excess MCM2-7 on chromosomes to promote initiation of DNA replication and is believed to be important for origin specification. Mapping of origins in cancer cell lines engineered to delete three of the subunits, ORC1, ORC2, or ORC5, shows that specific origins are still used and are mostly at the same sites in the genome as in wild-type cells. The few thousand origins that were upregulated in the absence of ORC suggest that GC/TA skewness and simple repeat sequences facilitate, but are not essential for, origin selection in the absence of the six-subunit ORC. Despite the lack of ORC, excess MCM2-7 is still loaded at comparable rates in G1 phase to license dormant origins and is also repeatedly loaded in the same S phase to permit re-replication. Thus, origin specification and excess MCM2-7 loading on origins do not require the six-subunit ORC in human cancer cell lines.
    DOI:  https://doi.org/10.1093/nar/gkaf518
  2. Nat Commun. 2025 Jun 18. 16(1): 5333
    USP37 prevents premature disassembly of stressed replisomes by TRAIP.
    Olga V Kochenova, Giuseppina D'Alessandro, Domenic Pilger, Ernst Schmid, Sean L Richards, Marcos Rios Garcia, Satpal S Jhujh, Andrea Voigt, Vipul Gupta, Christopher J Carnie, R Alex Wu, Nadia Gueorguieva, Simon Lam, Grant S Stewart, Johannes C Walter, Stephen P Jackson.
      The eukaryotic replisome, which consists of the CDC45-MCM2-7-GINS (CMG) helicase, replicative polymerases, and several accessory factors, sometimes encounters proteinaceous obstacles that threaten genome integrity. These obstacles are targeted for removal or proteolysis by the E3 ubiquitin ligase TRAIP, which associates with the replisome. However, TRAIP must be carefully regulated to avoid inappropriate ubiquitylation and disassembly of the replisome. Here, we demonstrate that human cells lacking the de-ubiquitylating enzyme USP37 are hypersensitive to topoisomerase poisons and other replication stress-inducing agents. Furthermore, TRAIP loss rescues the hypersensitivity of USP37 knockout cells to topoisomerase inhibitors. In Xenopus egg extracts depleted of USP37, TRAIP promotes premature CMG ubiquitylation and disassembly when converging replisomes stall. Finally, guided by AlphaFold-Multimer, we discovered that binding to CDC45 mediates USP37's response to topological stress. We propose that USP37 protects genome stability by preventing TRAIP-dependent CMG unloading when replication stress impedes timely termination.
    DOI:  https://doi.org/10.1038/s41467-025-60139-z
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