Ubiquitinated Fancd2 recruits Fan1 to stalled replication forks to prevent genome instability

Christophe Lachaud, Alberto Moreno, Francesco Marchesi, Rachel Toth, J. Julian Blow, John Rouse (Lead / Corresponding author)

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Mono-ubiquitination of Fancd2 is essential for repairing DNA interstrand cross-links (ICLs), but the underlying mechanisms are unclear. The Fan1 nuclease, also required for ICL repair, is recruited to ICLs by ubiquitinated (Ub) Fancd2. This could in principle explain how Ub-Fancd2 promotes ICL repair, but we show that recruitment of Fan1 by Ub-Fancd2 is dispensable for ICL repair. Instead, Fan1 recruitmentâ€"and activityâ€"restrains DNA replication fork progression and prevents chromosome abnormalities from occurring when DNA replication forks stall, even in the absence of ICLs. Accordingly, Fan1 nuclease-defective knockin mice are cancer-prone. Moreover, we show that a Fan1 variant in high-risk pancreatic cancers abolishes recruitment by Ub-Fancd2 and causes genetic instability without affecting ICL repair. Therefore, Fan1 recruitment enables processing of stalled forks that is essential for genome stability and health.

Original languageEnglish
Pages (from-to)846-849
Number of pages4
JournalScience
Volume351
Issue number6275
Early online date21 Jan 2016
DOIs
Publication statusPublished - 19 Feb 2016

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Genomic Instability
DNA Replication
Personnel Selection
Ubiquitination
Pancreatic Neoplasms
Chromosome Aberrations
DNA
Health
Neoplasms

Cite this

Lachaud, Christophe ; Moreno, Alberto ; Marchesi, Francesco ; Toth, Rachel ; Blow, J. Julian ; Rouse, John. / Ubiquitinated Fancd2 recruits Fan1 to stalled replication forks to prevent genome instability. In: Science. 2016 ; Vol. 351, No. 6275. pp. 846-849.
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Ubiquitinated Fancd2 recruits Fan1 to stalled replication forks to prevent genome instability. / Lachaud, Christophe; Moreno, Alberto; Marchesi, Francesco; Toth, Rachel; Blow, J. Julian; Rouse, John (Lead / Corresponding author).

In: Science, Vol. 351, No. 6275, 19.02.2016, p. 846-849.

Research output: Contribution to journalArticle

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