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

Lachaud, Christophe, Moreno, Alberto, Marchesi, Francesco, Toth, Rachel, Blow, J. Julian and Rouse, John (2016) Ubiquitinated Fancd2 recruits Fan1 to stalled replication forks to prevent genome instability. Science, 351 (6275). pp. 846-849. ISSN 0036-8075

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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.

Item Type:	Article
Uncontrolled Keywords:	sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School:
Depositing User:	LivePure Connector
Date Deposited:	10 Jun 2024 15:30
Last Modified:	17 Jun 2024 00:18
URI:	https://ueaeprints.uea.ac.uk/id/eprint/95460
DOI:	10.1126/science.aad5634

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