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Mechanism of Holliday junction resolution by the human GEN1 protein

journal contribution
posted on 2023-06-09, 15:11 authored by Ulrich RassUlrich Rass, Sarah A Compton, Joao Matos, Martin R Singleton, Stephen C Y Ip, Miguel G Blanco, Jack D Griffith, Stephen C West
Holliday junction (HJ) resolution is essential for chromosome segregation at meiosis and the repair of stalled/collapsed replication forks in mitotic cells. All organisms possess nucleases that promote HJ resolution by the introduction of symmetrically related nicks in two strands at, or close to, the junction point. GEN1, a member of the Rad2/XPG nuclease family, was isolated recently from human cells and shown to promote HJ resolution in vitro and in vivo. Here, we provide the first biochemical/structural characterization of GEN1, showing that, like the Escherichia coli HJ resolvase RuvC, it binds specifically to HJs and resolves them by a dual incision mechanism in which nicks are introduced in the pair of continuous (noncrossing) strands within the lifetime of the GEN1-HJ complex. In contrast to RuvC, but like other Rad2/XPG family members such as FEN1, GEN1 is a monomeric 5'-flap endonuclease. However, the unique feature of GEN1 that distinguishes it from other Rad2/XPG nucleases is its ability to dimerize on HJs. This functional adaptation provides the two symmetrically aligned active sites required for HJ resolution.

History

Publication status

  • Published

Journal

Genes & Development

ISSN

0890-9369

Publisher

Cold Spring Harbor Laboratory Press

Issue

14

Volume

24

Page range

1559-1569

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Research groups affiliated with

  • Genome Damage and Stability Centre Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2018-09-24

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