Structural and mechanistic insights into Mcm2-7 double-hexamer assembly and function

Sun, Jingchuan; Li, Huilin; Fernandez-Cid, Alejandra; Riera, Alberto; Tognetti, Sivia; Yuan, Zuanning; Stillman, Bruce; Speck, Christian

doi:10.1101/gad.242313.114

Structural and mechanistic insights into Mcm2-7 double-hexamer assembly and function

Journal Article · Wed Oct 15 00:00:00 EDT 2014 · Genes & Development

DOI:https://doi.org/10.1101/gad.242313.114· OSTI ID:1165733

Sun, Jingchuan ^[1]; Li, Huilin ^[2]; Fernandez-Cid, Alejandra ^[3]; Riera, Alberto ^[4]; Tognetti, Sivia ^[4]; Yuan, Zuanning ^[5]; Stillman, Bruce ^[6]; Speck, Christian ^[3]

Brookhaven National Laboratory (BNL), Upton, NY (United States)
Brookhaven National Laboratory (BNL), Upton, NY (United States); Stony Brook Univ., Stony Brook, NY (United States)
Imperial College Faculty of Medicine, London (United Kingdom). DNA Replication Group
Imperial College Faculty of Medicine, London (United Kingdom). MRC Clinical Sciences Centre
Stony Brook Univ., Stony Brook, NY (United States)
Cold Spring Harbor Lab., NY (United States)

Eukaryotic cells license each DNA replication origin during G1 phase by assembling a prereplication complex that contains a Mcm2–7 (minichromosome maintenance proteins 2–7) double hexamer. During S phase, each Mcm2–7 hexamer forms the core of a replicative DNA helicase. However, the mechanisms of origin licensing and helicase activation are poorly understood. The helicase loaders ORC–Cdc6 function to recruit a single Cdt1–Mcm2–7 heptamer to replication origins prior to Cdt1 release and ORC–Cdc6–Mcm2–7 complex formation, but how the second Mcm2–7 hexamer is recruited to promote double-hexamer formation is not well understood. Here, structural evidence for intermediates consisting of an ORC–Cdc6–Mcm2–7 complex and an ORC–Cdc6–Mcm2–7–Mcm2–7 complex are reported, which together provide new insights into DNA licensing. Detailed structural analysis of the loaded Mcm2–7 double-hexamer complex demonstrates that the two hexamers are interlocked and misaligned along the DNA axis and lack ATP hydrolysis activity that is essential for DNA helicase activity. Moreover, we show that the head-to-head juxtaposition of the Mcm2–7 double hexamer generates a new protein interaction surface that creates a multisubunit-binding site for an S-phase protein kinase that is known to activate DNA replication. The data suggest how the double hexamer is assembled and how helicase activity is regulated during DNA licensing, with implications for cell cycle control of DNA replication and genome stability.

View Accepted Manuscript (DOE)

Research Organization:: Brookhaven National Laboratory (BNL), Upton, NY (United States)

Sponsoring Organization:: National Institutes of Health

Grant/Contract Number:: AC02-98CH10886

OSTI ID:: 1165733

Report Number(s):: BNL--107184-2014-JA; 400412000

Journal Information:: Genes & Development, Journal Name: Genes & Development Journal Issue: 20 Vol. 28; ISSN 0890-9369

Publisher:: Cold Springs Harbor PressCopyright Statement

Country of Publication:: United States

Language:: English

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