Journal article

ATR-Mediated FANCI Phosphorylation Regulates Both Ubiquitination and Deubiquitination of FANCD2

Winnie Tan, Sylvie van Twest, Vincent J Murphy, Andrew J Deans

Frontiers in Cell and Developmental Biology | FRONTIERS MEDIA SA | Published : 2020

Abstract

DNA interstrand crosslinks (ICLs) are a physical barrier to replication and therefore toxic to cell viability. An important mechanism for the removal of ICLs is the Fanconi Anemia DNA repair pathway, which is initiated by mono-ubiquitination of FANCD2 and its partner protein FANCI. Here, we show that maintenance of FANCD2 and FANCI proteins in a monoubiquitinated form is regulated by the ATR-kinase. Using recombinant proteins in biochemical reconstitution experiments we show that ATR directly phosphorylates FANCI on serine 556, 559, and 565 to stabilize its association with DNA and FANCD2. This increased association with DNA stimulates the conjugation of ubiquitin to both FANCI and FANCD2, b..

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Grants

Awarded by National Health and Medical Research Council


Funding Acknowledgements

This work was supported by grants from the Fanconi Anemia Research Fund, the National Health and Medical Research Council (GNT1123100 and GNT1181110 to AD), and the Victoria government IOS program. WT was supported by an Australian Government Research Training Scheme postgraduate scholarship. AD was a Victorian Cancer Agency mid-career fellow.