FAN1 interaction with ubiquitylated PCNA alleviates replication stress and preserves genomic integrity independently of BRCA2

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Porro, Antonio 
Berti, Matteo 
Pizzolato, Julia 
Kaden, Svenja 

Interstrand cross-link (ICL) hypersensitivity is a characteristic trait of Fanconi anemia (FA). Although FANCD2-associated nuclease 1 (FAN1) contributes to ICL repair, FAN1 mutations predispose to karyomegalic interstitial nephritis (KIN) and cancer rather than to FA. Thus, the biological role of FAN1 remains unclear. Because fork stalling in FAN1-deficient cells causes chromosomal instability, we reasoned that the key function of FAN1 might lie in the processing of halted replication forks. Here, we show that FAN1 contains a previously-uncharacterized PCNA interacting peptide (PIP) motif that, together with its ubiquitin-binding zinc finger (UBZ) domain, helps recruit FAN1 to ubiquitylated PCNA accumulated at stalled forks. This prevents replication fork collapse and controls their progression. Furthermore, we show that FAN1 preserves replication fork integrity by a mechanism that is distinct from BRCA2-dependent homologous recombination. Thus, targeting FAN1 activities and its interaction with ubiquitylated PCNA may offer therapeutic opportunities for treatment of BRCA-deficient tumors.

BRCA2 Protein, Cell Line, Tumor, DNA Repair, DNA Replication, Endodeoxyribonucleases, Exodeoxyribonucleases, Humans, Multifunctional Enzymes, Proliferating Cell Nuclear Antigen, Protein Binding, Ubiquitination
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Nature Communications
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Springer Nature
This work was funded by the Swiss National Science Foundation (grant no. 310030B-133123 and 31003A- 149989) and by the European Research Council grant “Myriam” (294537), both to J.J.