DNSN-1 recruits GINS for CMG helicase assembly during DNA replication initiation in Caenorhabditis elegans .

Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 0404511 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1095-9203 (Electronic) Linking ISSN: 00368075 NLM ISO Abbreviation: Science Subsets: MEDLINE

Publication: : Washington, DC : American Association for the Advancement of Science
Original Publication: New York, N.Y. : [s.n.] 1880-

Caenorhabditis elegans*/genetics ; Caenorhabditis elegans*/metabolism ; DNA Replication* ; Minichromosome Maintenance Proteins*/chemistry ; Minichromosome Maintenance Proteins*/genetics ; Minichromosome Maintenance Proteins*/metabolism ; Caenorhabditis elegans Proteins*/chemistry ; Caenorhabditis elegans Proteins*/genetics ; Caenorhabditis elegans Proteins*/metabolism; Animals ; Cell Cycle Proteins/metabolism ; Cryoelectron Microscopy ; Chromosomal Proteins, Non-Histone/genetics ; Chromosomal Proteins, Non-Histone/metabolism ; Protein Domains

Assembly of the CMG (CDC-45-MCM-2-7-GINS) helicase is the key regulated step during eukaryotic DNA replication initiation. Until now, it was unclear whether metazoa require additional factors that are not present in yeast. In this work, we show that Caenorhabditis elegans DNSN-1, the ortholog of human DONSON, functions during helicase assembly in a complex with MUS-101/TOPBP1. DNSN-1 is required to recruit the GINS complex to chromatin, and a cryo-electron microscopy structure indicates that DNSN-1 positions GINS on the MCM-2-7 helicase motor (comprising the six MCM-2 to MCM-7 proteins), by direct binding of DNSN-1 to GINS and MCM-3, using interfaces that we show are important for initiation and essential for viability. These findings identify DNSN-1 as a missing link in our understanding of DNA replication initiation, suggesting that initiation defects underlie the human disease syndrome that results from DONSON mutations.

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MC_UP_1201/12 United Kingdom MRC_ Medical Research Council; 24558 United Kingdom CRUK_ Cancer Research UK; MC_UU_12016/13 United Kingdom MRC_ Medical Research Council; MC_UU_00018/4 United Kingdom MRC_ Medical Research Council; 21782 United Kingdom CRUK_ Cancer Research UK; DRCRPG-NOV22/100016 United Kingdom CRUK_ Cancer Research UK

0 (Cell Cycle Proteins)
0 (evl-18 protein, C elegans)
EC 3.6.4.12 (Minichromosome Maintenance Proteins)
0 (Caenorhabditis elegans Proteins)
0 (Chromosomal Proteins, Non-Histone)

Date Created: 20230817 Date Completed: 20230926 Latest Revision: 20250530

20250530

PMC7615117

10.1126/science.adi4932

37590372