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Karyomegalic Interstitial Nephritis and DNA Damage-Induced Polyploidy in Fan1 Nuclease-Defective Knock-In Mice

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Karyomegalic Interstitial Nephritis and DNA Damage-Induced Polyploidy in Fan1 Nuclease-Defective Knock-In Mice Downloaded from genesdev.cshlp.org on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press RESEARCH COMMUNICATION Fancd2 ubiquitylation (K561) causes defective ICL repair Karyomegalic interstitial (Garcia-Higuera et al. 2001; Knipscheer et al. 2009; Deans nephritis and DNA damage- and West 2011). Fan1 is a 5′ flap endonuclease recruited to sites where induced polyploidy in Fan1 replisomes stall—for example, at ICLs—in a manner that requires Fancd2 ubiquitylation (Kratz et al. 2010; Liu et al. nuclease-defective knock-in 2010; MacKay et al. 2010; Smogorzewska et al. 2010). The mice nuclease activities of Fan1 are mediated by a C-terminal “ ” 1 1 VRR_nuc domain (Iyer et al. 2006), which is conserved Christophe Lachaud, Meghan Slean, in all orthologs as far back as yeasts. Fan1 also has a SAP- Francesco Marchesi,2 Claire Lock,3 Edward Odell,3 type DNA-binding domain and a UBZ4-type ubiquitin- Dennis Castor,1,4 Rachel Toth,1 binding domain, which interacts with ubiquityl-Fancd2, and John Rouse1 thereby recruiting Fan1 to sites of replisome stalling. Fan1 is required for efficient ICL repair, but, surprisingly, 1MRC Protein Phosphorylation and Ubiquitylation Unit, College this does not require interaction with ubiquityl-Fancd2 of Life Sciences, Sir James Black Centre, University of Dundee, (Lachaud et al. 2016). Similarly, genetic analyses in worms Dundee DD1 5EH, United Kingdom 2School of Veterinary and human cells showed that Fan1 and Fancd2 mutations Medicine, College of Medical, Veterinary, and Life Sciences, are not epistatic with respect to hypersensitivity to ICL- University of Glasgow, Glasgow G61 1QH, United Kingdom inducing drugs, suggesting that the two genes are not 3Department of Head and Neck Pathology, Guy’s Hospital, equivalent in function when it comes to ICL repair (Yosh- London SE1 9RT, United Kingdom ikiyo et al. 2010; Zhou et al. 2012). Consistent with the idea that the role of Fan1 in ICL re- The Fan1 endonuclease is required for repair of DNA inter- pair is different from the FA pathway, biallelic mutations strand cross-links (ICLs). Mutations in human Fan1 cause in Fan1 do not cause FA. Instead, they cause a form of karyomegalic interstitial nephritis (KIN), but it is unclear chronic kidney disease referred to as karyomegalic inter- whether defective ICL repair is responsible or whether stitial nephritis (KIN) (Zhou et al. 2012). KIN is character- Fan1 nuclease activity is relevant. We show that Fan1 nu- ized by dilation and fibrosis of renal tubules with immune clease-defective (Fan1nd/nd) mice develop a mild form of cell invasion of interstitial spaces but differs from most KIN. The karyomegalic nuclei from Fan1nd/nd kidneys other forms of chronic kidney disease in that it is accom- are polyploid, and fibroblasts from Fan1nd/nd mice become panied by pronounced karyomegaly in the renal tubular epithelium (Godin et al. 1996). The cause of the karyome- polyploid upon ICL induction, suggesting that defective galy seen in KIN is not understood, and it is not clear ICL repair causes karyomegaly. Thus, Fan1 nuclease activ- whether this or any of the other characteristics of KIN ity promotes ICL repair in a manner that controls ploidy, in patients with Fan1 mutations is caused by defective a role that we show is not shared by the Fanconi anemia ICL repair. Furthermore, it is not clear whether the nucle- pathway or the Slx4–Slx1 nuclease also involved in ICL ase activity of Fan1 is required to prevent KIN, an issue repair. that we address in this study. Supplemental material is available for this article. Received December 9, 2015; revised version accepted Results and Discussion February 16, 2016. Fan1 nuclease-defective mice (Fan1nd/nd) exhibit hallmarks of KIN DNA interstrand cross-links (ICLs) are toxic lesions that To test the importance of the nuclease activity of Fan1 block the progression of replisomes. Defects in ICL repair for ICL repair, we introduced a Fan1-inactivating muta- are associated with Fanconi anemia (FA), a rare recessive tion in the mouse genome to make knock-in mice. Spe- disorder typified by developmental abnormalities, bone cifically, we introduced a mutation in the codon for marrow failure, and increased incidence of cancers (Auer- K975 in the VRR_nuc domain at the C terminus of bach 2009; Kim and D’Andrea 2012). There are currently Fan1 (Lachaud et al. 2016). This mutation also had the 19 genes known to cause FA when mutated, and studying consequence of inhibiting splicing of exon 13 with the products of the FA genes has shed important insights exon 14 (the last Fan1 exon), resulting in intron retention into how ICLs are repaired. A central event in ICL repair and deletion of the last 41 amino acids of Fan1, including is the monoubiquitylation of Fancd2 catalyzed by the several residues essential for catalysis (Lachaud et al. multisubunit FA core complex, which acts as an E3 ubiq- 2016). Consequently, the truncated form of Fan1 encod- uitin ligase in concert with Ube2t (Akkari et al. 2000; ed by the Fan1-nd allele is devoid of nuclease activity Garcia-Higuera et al. 2001; Alpi et al. 2008). Preventing (Supplemental Fig. S1). Mouse embryonic fibroblasts (MEFs) isolated from homozygous Fan1nd/nd mice are [Keywords: FAN1; FANCD2; ICL; Fanconi anemia; KIN; karyomegaly] profoundly hypersensitive to ICL-inducing genotoxins, 4Present address: Meda Pharma Gmbh and Company, 61352, Bad Hom- but MEFs from Fan1+/nd mice are not, indicating that burg, Germany. Corresponding author: [email protected] Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.276287. © 2016 Lachaud et al. This article, published in Genes & Development,is 115. Freely available online through the Genes & Development Open Ac- available under a Creative Commons License (Attribution 4.0 Internation- cess option. al), as described at http://creativecommons.org/licenses/by/4.0/. GENES & DEVELOPMENT 30:639–644 Published by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/16; www.genesdev.org 639 Downloaded from genesdev.cshlp.org on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Lachaud et al. the nuclease-dead Fan1 mutant does not act in a domi- role in the processing of stalled forks independent of nant-negative manner (Fig. 1A). MEFs from Fan1nd/nd ICL repair (Lachaud et al. 2016). +/nd nd/nd mice also show pronounced G2 arrest after exposure to Fan1 and Fan1 mice were born at the expected mitomycin C (MMC) or diepoxybutane (DEB) (Supple- Mendelian frequencies (Supplemental Table S1) without mental Fig. S2A). These data show that Fan1 nuclease ac- overt morphological, developmental, or hematological de- tivity is important for ICL repair. MEFs from Fan1nd/nd fects, and adult mice were fertile (data not shown). How- mice also show an increase in the frequency of chromo- ever, we observed signs of KIN in Fan1nd/nd mice, and some abnormalities after MMC or DEB (Supplemental the most notable feature was prominent karyomegaly in Fig. S2B), a defect that was recently shown to reflect a the renal tubular epithelium, coincident with positive γ- H2AX staining (Fig. 1B,C). Karyomegaly was evident at 6 mo of age and worse by 20 mo (Fig. 1B,C; Supplemental Table S2). Renal histopathology also revealed an increased incidence of a spectrum of tubular changes, particularly in 100 A Fan1+/+ older mice, including dilation, degeneration, and atrophy, Fan1+/nd along with increased infiltration of inflammatory cells in 10 Fan1nd/nd interstitial spaces (Fig. 1B; Supplemental Table S2). Fur- 1 thermore, tubules in the older mice were frequently char- Cell survival (%) acterized by thickening of the basement membranes (Fig. 0.1 0 20406080 1B; Supplemental Table S2). MMC (ng/ml) To understand the nature of the karyomegaly in nd/nd B Fan1 mice, we measured the DNA content of nuclei tubular dilatation/ basement membrane isolated from kidney sections. Nuclei from Fan1+/nd mice atrophy thickening were diploid with a single peak at 2n, minimal G2 popu- lation (4n), and no detectable S-phase population (Fig. 1E). On the other hand, nuclei from Fan1nd/nd mice showed an increased population with 4n DNA content and a minority of nuclei with 8n content, suggestive of whole-genome or near-whole-genome doublings with- out division in a subset of cells (Fig. 1E; Supplemental Fig. S3). Taken together, these data show that Fan1 nu- clease activity is critical for preventing alterations in ploidy in the renal tubular epithelium and preventing symptoms of KIN. karyomegaly -H2AX C D nd/nd 100 100 Polyploidy in MEFs from Fan1 mice upon 6 month old 20 month old 6 month old 20 month old 80 80 ICL induction 60 60 nd/nd 40 40 Karyomegaly in the kidneys of Fan1 mice may be 20 20 a consequence of unrepaired ICLs that arise in kidneys 0 Karyomegalic cells Karyomegalic 0 -H2AX positive cells through continuous filtration of genotoxic waste com- Fan1 +/nd nd/nd +/nd nd/nd Fan1 +/nd nd/nd +/nd nd/nd pounds. We reasoned that embryonic fibroblasts from Fan1nd/nd mice would not have sustained such a high E level of genotoxic insult but may become polyploid +/nd upon ICL induction. As shown in Figure 2A, exposure 1600 Fan1+/nd 1200 Fan1 nd/nd Diploid of primary MEFs from Fan1 mice, but not from Diploid 900 1200 control Fan1+/+ mice, led to a modest but significant in- 800 600 crease in the proportion of cells with 8n DNA content, 400 300 reminiscent of the ploidy changes observed in kidneys Nb of nuclei (au) 30 µM Nuclei >5C Nuclei >4C 30 µM nd/nd Nb of nuclei (au) 0 0 from Fan1 mice (Fig. 1E; Supplemental Fig. S3). 02C4C 8C 0 2C 4C 8C integrated OD integrated OD These changes in ploidy after MMC were consistently observed in primary Fan1nd/nd MEFs but not once the Figure 1.
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