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FAN1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4REA, 4REB, 4REC, 4RI8, 4RI9, 4RIA, 4RIB, 4RIC, 4RID, 4RY3
Identifiers
Aliases	FAN1, KIAA1018, KMIN, MTMR15, hFANCD2/FANCI-associated nuclease 1, FANCD2 and FANCI associated nuclease 1
External IDs	OMIM: 613534; MGI: 3045266; HomoloGene: 45598; GeneCards: FAN1; OMA:FAN1 - orthologs
Gene location (Human) Chr. Chromosome 15 (human) Band 15q13.3 Start 30,890,559 bp End 30,943,108 bp
Gene location (Mouse) Chr. Chromosome 7 (mouse) Band 7|7 C Start 63,996,506 bp End 64,023,843 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right hemisphere of cerebellum gastrocnemius muscle ventricular zone body of pancreas ganglionic eminence muscle of thigh right uterine tube left ovary gonad right frontal lobe Top expressed in quadriceps femoris muscle muscle of thigh ganglionic eminence epiblast muscle tissue white adipose tissue liver Hypothalamus skeletal muscle tissue ventricular zone More reference expression data BioGPS n/a
Gene ontology Molecular function DNA binding hydrolase activity, acting on ester bonds phosphodiesterase I activity 5'-3' exonuclease activity flap-structured DNA binding metal ion binding 5'-flap endonuclease activity protein binding nuclease activity endonuclease activity exonuclease activity hydrolase activity magnesium ion binding ubiquitin-dependent protein binding nucleic acid binding Cellular component nucleoplasm intercellular bridge nucleus cytosol Biological process nucleotide-excision repair cellular response to DNA damage stimulus double-strand break repair via homologous recombination nucleotide-excision repair, DNA incision DNA repair interstrand cross-link repair nucleic acid phosphodiester bond hydrolysis Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 22909 330554 Ensembl ENSG00000276787 ENSG00000198690 ENSMUSG00000033458 UniProt Q9Y2M0 Q69ZT1 RefSeq (mRNA) NM_001146094 NM_001146095 NM_001146096 NM_014967 NM_177893 RefSeq (protein) NP_001139566 NP_001139567 NP_001139568 NP_055782 NP_808561 Location (UCSC) Chr 15: 30.89 – 30.94 Mb Chr 7: 64 – 64.02 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

FANCD2/FANCI-associated nuclease 1 (KIAA1018) is an enzyme that in humans is encoded by the FAN1 gene. It is a structure dependent endonuclease. It is thought to play an important role in the Fanconi Anemia (FA) pathway.

Structure

FAN1 is a protein of 1017 amino acids. Several crystal structures of the residues 373-1017 have been characterized. This portion of FAN1 contains three domains: an SAP domain (primary-DNA binding domain), a TPR domain (mediating interdomain interaction and dimerization interface) and the virus-type replication-repair nuclease module (VRR_NUC, catalytic site) (Figure 1). DNA binding promotes dimerization of FAN1 in a "head to tail" fashion.

The SAP region contains three major components: α₉, α₅β₁, and α₇. The core helix α₉ stabilizes the protein as it moves through dimer configurations and mediates the interactions between α₅β₁ and α₇ as they adjust their positions. These three configurations are the substrate scanning, substrate latching and substrate unwinding forms (figure 2).

In the FAN1 dimer, the SAP regions of both FAN1 enzymes make contact with the DNA duplex (dsDNA). This double contact facilitates DNA induced dimerization, as well as guiding the single stranded (ssDNA) into the SAP domain of the downstream enzyme (SAP). The SAP domain of the upstream FAN1 component enzyme (SAP) aids in guiding the DNA to SAP.

The SAP surface facing the catalytic site is the most conserved region between FAN1 homologs. It is positively charged for favorable hydrogen bonding and electrostatic interactions with DNA. In particular, residues Y374 and Y436 form hydrogen bonds with the phosphate backbone. FAN1 can bind DNA in either direction. However, when the 5' flab is facing away from the VRR_NUC site, substrate latching and unwinding cannot occur. The unresolved portion of FAN1 contains a Zinc finger at the N terminus called a UBZ region. This is present in proteins that bind to ubiquitinated proteins, and is highly conserved across eukaryotes. This Zinc finger is crucial for recruitment to the ubiquitinated FANCD2/FANCI complex, and is found in other nucleases. The VRR_Nuc catalytic domain is located at the C terminus and contains the endonuclease functionality. FAN1 is the first known instance of a virus type replication-repair nuclease module in eukaryotes. It is normally found as a standalone domain in bacterial and viral Holliday Junction Resolvases (HJR). FAN1 does not exhibit any activity on Holliday Junction (HJ) substrates. A subdomain of SAP consisting of six α helices connected to the VRR_Nuc region is thought to inhibit HJR activity.

Function

Interstrand DNA crosslinks (ICLs) effectively block the progression of transcription and replication machineries. Release of this block, referred to as unhooking, is thought to require incision of one strand of the duplex on either side of the ICL.

Repair of interstrand DNA crosslinks is triggered when the DNA replication fork is unable to continue. The FA proteins play an elaborate role with FAN1 to remove these ICLs. The pathway consists of 15 known proteins. Three of them form the FA AP24-MHF1/2 complex which recognizes the ICL (from stalled replication forks). This recruits the FA core complex, which consists of 8 proteins. This complex monoubiquitinates FANCD2 and FANCI, which allows it to form a heterodimer. It is this complex that recruits FAN1 as well as other nucleases such as SLX4. Ubiquinated FANCD2 interacts with the FAN1 nuclease. Upon its recruitment by FANCD2, FAN1 acts to restrain DNA replication fork progression and to prevent chromosome abnormalities from occurring when DNA replication forks stall. FAN1 is typically localized in the nucleus, but forms very distinct loci at damaged regions when ICLs are present.

The FAN1 protein possesses endonuclease and exonuclease functions to remove ICLs. At a replication fork arrested at an ICL, FAN1 nuclease action can catalyze incisions in the double-stranded region. It is thought that this process consists of unhooking the crosslink and separating the DNA strands through two incision events, yielding one strand with a crosslinked nucleotide and another strand with a gap. FAN1 preferentially acts as a 5’ flap endonuclease. This is illustrated in Figure 2, which shows the sequence of substrate scanning, latching, and unwinding. It usually cleaves about 5 nucleotides from a junction. FAN1 will also incise at splayed arms, three way junctions, and 3’ flaps (in order of decreasing preference). In high concentrations FAN1 has been shown to exhibit 3’ 5’ exonuclease activity. In blunt end substrates, FAN1 has also 5’ recessed ends. However, FAN1 does not appear to bind to single stranded DNA.

The presence of the FANCD2/FANCI complex is unaffected by knockdown of FAN1. This is because FAN1 acts downstream to the recruitment of FANCD2/FANCI. FAN1 has also been shown to increase the frequency of homologous recombination. This suggests that the gapped intermediate that forms following ICL unhooking may be repaired through HR when homologous chromosomes are present. FAN1 does not appear to be involved in other types of DNA repair, as it does not localize to DNA upon irradiation.

Clinical significance

Mutations affecting the function of the 15 known FA genes are associated with Fanconi anemia, a recessive autosomal disorder. It is characterized by congenital abnormalities as well as anemia, bone marrow failure, and cancer predisposition in childhood. However, some patients have “unassigned” Fanconi Anemia where no mutations in the known FA genes can be found. Mutations in FAN1 can result in chronic kidney diseases and neurological conditions such as schizophrenia. However, recent research has called into question the categorization of FAN1 as an FA gene. In 2015 researchers studied four individuals with chromosomal microdeletion of 15q13.3. Analysis of blood samples revealed only mild ICL agent sensitivity and chromosomal fragility consistent with Fanconi Anemia.

A deficiency of FAN1 increases in vitro sensitivity to cisplatin and mitomycin C, two crosslinking agents FAN1 is also able to repair mitomycin C induced double strand breaks.

Germline mutations in the FAN1 gene can cause hereditary colorectal cancer due to defective DNA repair.

References

1. ^ ENSG00000198690 GRCh38: Ensembl release 89: ENSG00000276787, ENSG00000198690 – Ensembl, May 2017
2. ^ GRCm38: Ensembl release 89: ENSMUSG00000033458 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: FANCD2/FANCI-associated nuclease 1".
6. ^ Zhao Q, Xue X, Longerich S, Sung P, Xiong Y (December 2014). "Structural insights into 5' flap DNA unwinding and incision by the human FAN1 dimer". Nature Communications. 5 (11): 5726. Bibcode:2014NatCo...5.5726Z. doi:10.1038/ncomms6726. PMC 4268874. PMID 25500724.
7. ^ MacKay C, Déclais AC, Lundin C, Agostinho A, Deans AJ, MacArtney TJ, et al. (July 2010). "Identification of KIAA1018/FAN1, a DNA repair nuclease recruited to DNA damage by monoubiquitinated FANCD2". Cell. 142 (1): 65–76. doi:10.1016/j.cell.2010.06.021. PMC 3710700. PMID 20603015.
8. ^ Pennell S, Déclais AC, Li J, Haire LF, Berg W, Saldanha JW, et al. (July 2014). "FAN1 activity on asymmetric repair intermediates is mediated by an atypical monomeric virus-type replication-repair nuclease domain". Cell Reports. 8 (1): 84–93. doi:10.1016/j.celrep.2014.06.001. PMC 4103454. PMID 24981866.
9. ^ Kim H, D'Andrea AD (July 2012). "Regulation of DNA cross-link repair by the Fanconi anemia/BRCA pathway". Genes & Development. 26 (13): 1393–408. doi:10.1101/gad.195248.112. PMC 3403008. PMID 22751496.
10. Wang R, Persky NS, Yoo B, Ouerfelli O, Smogorzewska A, Elledge SJ, Pavletich NP (November 2014). "DNA repair. Mechanism of DNA interstrand cross-link processing by repair nuclease FAN1". Science. 346 (6213): 1127–30. doi:10.1126/science.1258973. PMC 4285437. PMID 25430771.
11. Lachaud C, Moreno A, Marchesi F, Toth R, Blow JJ, Rouse J (February 2016). "Ubiquitinated Fancd2 recruits Fan1 to stalled replication forks to prevent genome instability". Science. 351 (6275): 846–9. Bibcode:2016Sci...351..846L. doi:10.1126/science.aad5634. PMC 4770513. PMID 26797144.
12. ^ Shereda RD, Machida Y, Machida YJ (October 2010). "Human KIAA1018/FAN1 localizes to stalled replication forks via its ubiquitin-binding domain". Cell Cycle. 9 (19): 3977–83. doi:10.4161/cc.9.19.13207. PMID 20935496.
13. Pizzolato J, Mukherjee S, Schärer OD, Jiricny J (September 2015). "FANCD2-associated nuclease 1, but not exonuclease 1 or flap endonuclease 1, is able to unhook DNA interstrand cross-links in vitro". The Journal of Biological Chemistry. 290 (37): 22602–11. doi:10.1074/jbc.M115.663666. PMC 4566234. PMID 26221031.
14. Smogorzewska A, Desetty R, Saito TT, Schlabach M, Lach FP, Sowa ME, et al. (July 2010). "A genetic screen identifies FAN1, a Fanconi anemia-associated nuclease necessary for DNA interstrand crosslink repair". Molecular Cell. 39 (1): 36–47. doi:10.1016/j.molcel.2010.06.023. PMC 2919743. PMID 20603073.
15. Kee Y, D'Andrea AD (August 2010). "Expanded roles of the Fanconi anemia pathway in preserving genomic stability". Genes & Development. 24 (16): 1680–94. doi:10.1101/gad.1955310. PMC 2922498. PMID 20713514.
16. ^ Sengerová B, Wang AT, McHugh PJ (December 2011). "Orchestrating the nucleases involved in DNA interstrand cross-link (ICL) repair". Cell Cycle. 10 (23): 3999–4008. doi:10.4161/cc.10.23.18385. PMC 3272282. PMID 22101340.
17. ^ Liu T, Ghosal G, Yuan J, Chen J, Huang J (August 2010). "FAN1 acts with FANCI-FANCD2 to promote DNA interstrand cross-link repair". Science. 329 (5992): 693–6. Bibcode:2010Sci...329..693L. doi:10.1126/science.1192656. PMID 20671156. S2CID 206527789.
18. Zhou W, Otto EA, Cluckey A, Airik R, Hurd TW, Chaki M, et al. (July 2012). "FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair". Nature Genetics. 44 (8): 910–5. doi:10.1038/ng.2347. PMC 3412140. PMID 22772369.
19. Trujillo JP, Mina LB, Pujol R, Bogliolo M, Andrieux J, Holder M, et al. (July 2012). "On the role of FAN1 in Fanconi anemia". Blood. 120 (1): 86–9. doi:10.1182/blood-2012-04-420604. PMID 22611161.
20. Seguí N, Mina LB, Lázaro C, Sanz-Pamplona R, Pons T, Navarro M, et al. (September 2015). "Germline Mutations in FAN1 Cause Hereditary Colorectal Cancer by Impairing DNA Repair". Gastroenterology. 149 (3): 563–6. doi:10.1053/j.gastro.2015.05.056. hdl:10651/34223. PMID 26052075.

Further reading

• Yoshikiyo K, Kratz K, Hirota K, Nishihara K, Takata M, Kurumizaka H, et al. (December 2010). "KIAA1018/FAN1 nuclease protects cells against genomic instability induced by interstrand cross-linking agents". Proceedings of the National Academy of Sciences of the United States of America. 107 (50): 21553–7. Bibcode:2010PNAS..10721553Y. doi:10.1073/pnas.1011081107. PMC 3003052. PMID 21115814.
• Park DJ, Odefrey FA, Hammet F, Giles GG, Baglietto L, Hopper JL, et al. (December 2011). "FAN1 variants identified in multiple-case early-onset breast cancer families via exome sequencing: no evidence for association with risk for breast cancer". Breast Cancer Research and Treatment. 130 (3): 1043–9. doi:10.1007/s10549-011-1704-y. PMID 21858661. S2CID 10887801.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

• Biology

• Genes on human chromosome 15
• EC 3.1.4