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Nat Commun. 2017 Oct 20;8(1):1073. doi: 10.1038/s41467-017-01074-6.

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

Author information

1
Institute of Molecular Cancer Research of the University of Zurich and ETH Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland. porro@imcr.uzh.ch.
2
Institute of Molecular Cancer Research of the University of Zurich and ETH Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland.
3
Wellcome Trust/Cancer Research UK Gurdon Institute, Tennis Court Road, Cambridge, CB2 1QN, UK.
4
Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16 Naka-cho, Koganei-shi, Tokyo, 184-8588, Japan.
5
Institute of Molecular Cancer Research of the University of Zurich and ETH Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland. sartori@imcr.uzh.ch.
6
Institute of Molecular Cancer Research of the University of Zurich and ETH Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland. jjiricny@ethz.ch.
7
Institute of Molecular Life Sciences of the University of Zurich and Institute of Biochemistry of the ETH Zurich, Otto-Stern-Weg 3, Zurich, 8093, Switzerland. jjiricny@ethz.ch.

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.

PMID:
29051491
PMCID:
PMC5648898
DOI:
10.1038/s41467-017-01074-6
[Indexed for MEDLINE]
Free PMC Article

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