Mutations of the SLX4 Gene in Fanconi Anemia

Overview

Journal Nat Genet

Specialty Genetics

Date 2011 Jan 18

PMID 21240275

Citations 198

Authors

YongHwan Kim

Francis P Lach

Rohini Desetty

Helmut Hanenberg

Arleen D Auerbach

Agata Smogorzewska

Affiliations

Soon will be listed here.

Abstract

Fanconi anemia is a rare recessive disorder characterized by genome instability, congenital malformations, progressive bone marrow failure and predisposition to hematologic malignancies and solid tumors. At the cellular level, hypersensitivity to DNA interstrand crosslinks is the defining feature in Fanconi anemia. Mutations in thirteen distinct Fanconi anemia genes have been shown to interfere with the DNA-replication-dependent repair of lesions involving crosslinked DNA at stalled replication forks. Depletion of SLX4, which interacts with multiple nucleases and has been recently identified as a Holliday junction resolvase, results in increased sensitivity of the cells to DNA crosslinking agents. Here we report the identification of biallelic SLX4 mutations in two individuals with typical clinical features of Fanconi anemia and show that the cellular defects in these individuals' cells are complemented by wildtype SLX4, demonstrating that biallelic mutations in SLX4 (renamed here as FANCP) cause a new subtype of Fanconi anemia, Fanconi anemia-P.

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References

Moldovan G, DAndrea A . How the fanconi anemia pathway guards the genome. Annu Rev Genet. 2009; 43:223-49. PMC: 2830711. DOI: 10.1146/annurev-genet-102108-134222. View

Kratz K, Schopf B, Kaden S, Sendoel A, Eberhard R, Lademann C . Deficiency of FANCD2-associated nuclease KIAA1018/FAN1 sensitizes cells to interstrand crosslinking agents. Cell. 2010; 142(1):77-88. DOI: 10.1016/j.cell.2010.06.022. View

Seal S, Thompson D, Renwick A, Elliott A, Kelly P, Barfoot R . Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat Genet. 2006; 38(11):1239-41. DOI: 10.1038/ng1902. View

Svendsen J, Smogorzewska A, Sowa M, OConnell B, Gygi S, Elledge S . Mammalian BTBD12/SLX4 assembles a Holliday junction resolvase and is required for DNA repair. Cell. 2009; 138(1):63-77. PMC: 2720686. DOI: 10.1016/j.cell.2009.06.030. View

Hofmann K . Ubiquitin-binding domains and their role in the DNA damage response. DNA Repair (Amst). 2009; 8(4):544-56. DOI: 10.1016/j.dnarep.2009.01.003. View

Fekairi S, Scaglione S, Chahwan C, Taylor E, Tissier A, Coulon S . Human SLX4 is a Holliday junction resolvase subunit that binds multiple DNA repair/recombination endonucleases. Cell. 2009; 138(1):78-89. PMC: 2861413. DOI: 10.1016/j.cell.2009.06.029. View

Munoz I, Hain K, Declais A, Gardiner M, Toh G, Sanchez-Pulido L . Coordination of structure-specific nucleases by human SLX4/BTBD12 is required for DNA repair. Mol Cell. 2009; 35(1):116-27. DOI: 10.1016/j.molcel.2009.06.020. View

Howlett N, Taniguchi T, Olson S, Cox B, Waisfisz Q, de Die-Smulders C . Biallelic inactivation of BRCA2 in Fanconi anemia. Science. 2002; 297(5581):606-9. DOI: 10.1126/science.1073834. View

Auerbach A . Fanconi anemia and its diagnosis. Mutat Res. 2009; 668(1-2):4-10. PMC: 2742943. DOI: 10.1016/j.mrfmmm.2009.01.013. View

10.

Ciccia A, McDonald N, West S . Structural and functional relationships of the XPF/MUS81 family of proteins. Annu Rev Biochem. 2008; 77:259-87. DOI: 10.1146/annurev.biochem.77.070306.102408. View

11.

Knipscheer P, Raschle M, Smogorzewska A, Enoiu M, Ho T, Scharer O . The Fanconi anemia pathway promotes replication-dependent DNA interstrand cross-link repair. Science. 2009; 326(5960):1698-701. PMC: 2909596. DOI: 10.1126/science.1182372. View

12.

Lamesch P, Li N, Milstein S, Fan C, Hao T, Szabo G . hORFeome v3.1: a resource of human open reading frames representing over 10,000 human genes. Genomics. 2007; 89(3):307-15. PMC: 4647941. DOI: 10.1016/j.ygeno.2006.11.012. View

13.

Xia B, Dorsman J, Ameziane N, de Vries Y, Rooimans M, Sheng Q . Fanconi anemia is associated with a defect in the BRCA2 partner PALB2. Nat Genet. 2007; 39(2):159-61. DOI: 10.1038/ng1942. View

14.

Vaz F, Hanenberg H, Schuster B, Barker K, Wiek C, Erven V . Mutation of the RAD51C gene in a Fanconi anemia-like disorder. Nat Genet. 2010; 42(5):406-9. DOI: 10.1038/ng.570. View

15.

Sobhian B, Shao G, Lilli D, Culhane A, Moreau L, Xia B . RAP80 targets BRCA1 to specific ubiquitin structures at DNA damage sites. Science. 2007; 316(5828):1198-202. PMC: 2706583. DOI: 10.1126/science.1139516. View

16.

Garcia-Higuera I, Taniguchi T, Ganesan S, Meyn M, Timmers C, Hejna J . Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway. Mol Cell. 2001; 7(2):249-62. DOI: 10.1016/s1097-2765(01)00173-3. View

17.

Dolma S, Lessnick S, Hahn W, Stockwell B . Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. Cancer Cell. 2003; 3(3):285-96. DOI: 10.1016/s1535-6108(03)00050-3. View

18.

Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J . Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995; 378(6559):789-92. DOI: 10.1038/378789a0. View

19.

Smogorzewska A, Desetty R, Saito T, Schlabach M, Lach F, Sowa M . A genetic screen identifies FAN1, a Fanconi anemia-associated nuclease necessary for DNA interstrand crosslink repair. Mol Cell. 2010; 39(1):36-47. PMC: 2919743. DOI: 10.1016/j.molcel.2010.06.023. View

20.

MacKay C, Declais A, Lundin C, Agostinho A, Deans A, Macartney T . Identification of KIAA1018/FAN1, a DNA repair nuclease recruited to DNA damage by monoubiquitinated FANCD2. Cell. 2010; 142(1):65-76. PMC: 3710700. DOI: 10.1016/j.cell.2010.06.021. View