CUL-2^LRR-1 and UBXN-3 drive replisome disassembly during DNA replication termination and mitosis

TY - JOUR

T1 - CUL-2LRR-1 and UBXN-3 drive replisome disassembly during DNA replication termination and mitosis

AU - Sonneville, Remi

AU - Priego Moreno, Sara

AU - Knebel, Axel

AU - Johnson, Clare

AU - Hastie, C. James

AU - Gartner, Anton

AU - Gambus, Agnieszka

AU - Labib, Karim

N1 - We gratefully acknowledge the support of the Medical Research Council (core grant MC_UU_12016/13 for KL; award MR/K007106/1 to Agnieszka Gambus) the Wellcome Trust (reference 102943/Z/13/Z for award to KL; reference 0909444/Z/09/Z for award to Anton Gartner) and the Lister Institute (award to Agnieszka Gambus) for funding our work.

PY - 2017/4/3

Y1 - 2017/4/3

N2 - Replisome disassembly is the final step of DNA replication in eukaryotes, involving the ubiquitylation and CDC48-dependent dissolution of the CMG helicase (Cdc45-MCM-GINS). Using Caenorhabditis elegans early embryos and Xenopus egg extracts, we show that the E3 ligase CUL-2LRR-1 associates with the replisome and drives ubiquitylation and disassembly of CMG, together with the CDC-48 co-factors UFD-1 and NPL-4. Removal of CMG from chromatin in frog egg extracts requires CUL2 neddylation, and our data identify chromatin recruitment of CUL2LRR1 as a key regulated step during DNA replication termination. Interestingly, however, CMG persists on chromatin until prophase in worms that lack CUL-2LRR-1, but is then removed by a mitotic pathway that requires the CDC-48 co-factor UBXN-3, orthologous to the human tumour suppressor FAF1. Partial inactivation of lrr-1 and ubxn-3 leads to synthetic lethality, suggesting future strategies by which a deeper understanding of CMG disassembly in metazoa could be exploited therapeutically.

AB - Replisome disassembly is the final step of DNA replication in eukaryotes, involving the ubiquitylation and CDC48-dependent dissolution of the CMG helicase (Cdc45-MCM-GINS). Using Caenorhabditis elegans early embryos and Xenopus egg extracts, we show that the E3 ligase CUL-2LRR-1 associates with the replisome and drives ubiquitylation and disassembly of CMG, together with the CDC-48 co-factors UFD-1 and NPL-4. Removal of CMG from chromatin in frog egg extracts requires CUL2 neddylation, and our data identify chromatin recruitment of CUL2LRR1 as a key regulated step during DNA replication termination. Interestingly, however, CMG persists on chromatin until prophase in worms that lack CUL-2LRR-1, but is then removed by a mitotic pathway that requires the CDC-48 co-factor UBXN-3, orthologous to the human tumour suppressor FAF1. Partial inactivation of lrr-1 and ubxn-3 leads to synthetic lethality, suggesting future strategies by which a deeper understanding of CMG disassembly in metazoa could be exploited therapeutically.

KW - DNA replication termination

KW - replisome disassembly

KW - CMG 18 helicase

KW - Caenorhabditis elegans

KW - Xenopus laevis

KW - Cullin

KW - CUL-2

KW - LRR-1

KW - UBXN-3

KW - FAF1

KW - CUL2

KW - LRR1

KW - CDC-48, UFD-1

KW - NPL-4

KW - p97

KW - VCP

KW - ULP-4

U2 - 10.1038/ncb3500

DO - 10.1038/ncb3500

M3 - Article

C2 - 28368371

SN - 1465-7392

VL - 19

SP - 468

EP - 479

JO - Nature Cell Biology

JF - Nature Cell Biology

ER -