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

Research output: Contribution to journalArticlepeer-review


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
Issue number6275
Publication statusPublished - 21 Jan 2016

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