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

Antonio Porro (), Matteo Berti, Julia Pizzolato, Serena Bologna, Svenja Kaden, Anja Saxer, Yue Ma, Kazuo Nagasawa, Alessandro A. Sartori () and Josef Jiricny ()
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Antonio Porro: Institute of Molecular Cancer Research of the University of Zurich and ETH Zurich
Matteo Berti: Institute of Molecular Cancer Research of the University of Zurich and ETH Zurich
Julia Pizzolato: Institute of Molecular Cancer Research of the University of Zurich and ETH Zurich
Serena Bologna: Institute of Molecular Cancer Research of the University of Zurich and ETH Zurich
Svenja Kaden: Institute of Molecular Cancer Research of the University of Zurich and ETH Zurich
Anja Saxer: Institute of Molecular Cancer Research of the University of Zurich and ETH Zurich
Yue Ma: Tokyo University of Agriculture and Technology
Kazuo Nagasawa: Tokyo University of Agriculture and Technology
Alessandro A. Sartori: Institute of Molecular Cancer Research of the University of Zurich and ETH Zurich
Josef Jiricny: Institute of Molecular Cancer Research of the University of Zurich and ETH Zurich

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/s41467-017-01074-6

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