TY  - JOUR
A1  - Rickman, Kimberly A.
A1  - Lach, Francis P.
A1  - Abhyankar, Avinash
A1  - Donovan, Frank X.
A1  - Sanborn, Erica M.
A1  - Kennedy, Jennifer A.
A1  - Sougnez, Carrie
A1  - Gabriel, Stacey B.
A1  - Elemento, Olivier
A1  - Chandrasekharappa, Settara C.
A1  - Schindler, Detlev
A1  - Auerbach, Arleen D.
A1  - Smogorzewska, Agata
T1  - Deficiency of UBE2T, the E2 Ubiquitin Ligase Necessary for FANCD2 and FANCI Ubiquitination, Causes FA-T Subtype of Fanconi Anemia
JF  - Cell Reports
N2  - Fanconi anemia (FA) is a rare bone marrow failure and cancer predisposition syndrome resulting from pathogenic mutations in genes encoding proteins participating in the repair of DNA interstrand crosslinks (ICLs). Mutations in 17 genes (FANCA-FANCS) have been identified in FA patients, defining 17 complementation groups. Here, we describe an individual presenting with typical FA features who is deficient for the ubiquitin-conjugating enzyme (E2), UBE2T. UBE2T is known to interact with FANCL, the E3 ubiquitin-ligase component of the multiprotein FA core complex, and is necessary for the monoubiquitination of FANCD2 and FANCI. Proband fibroblasts do not display FANCD2 and FANCI monoubiquitination, do not form FANCD2 foci following treatment with mitomycin C, and are hypersensitive to crosslinking agents. These cellular defects are complemented by expression of wild-type UBE2T, demonstrating that deficiency of the protein UBE2T can lead to Fanconi anemia. UBE2T gene gains an alias of FANCT.
KW  - cross-link repair
KW  - DNA repair
KW  - gene
KW  - mutations
KW  - aldehydes
KW  - somatic mosaicism
KW  - pathway
KW  - monoubiquitination
KW  - diagnosis
KW  - proteins
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151525
VL  - 12
SP  - 35
EP  - 41
ER  - 
TY  - JOUR
A1  - Fernández-Rodríguez, Juana
A1  - Quiles, Francisco
A1  - Blanco, Ignacio
A1  - Teulé, Alex
A1  - Feliubadaló, Lídia
A1  - del Valle, Jesús
A1  - Salinas, Mónica
A1  - Izquierdo, Ángel
A1  - Darder, Esther
A1  - Schindler, Detlev
A1  - Capellá, Gabriel
A1  - Brunet, Joan
A1  - Lázaro, Conxi
A1  - Angel Pujana, Miguel
T1  - Analysis of SLX4/FANCP in non-BRCA1/2-mutated breast cancer families
JF  - BMC Cancer
N2  - Background: Genes that, when mutated, cause Fanconi anemia or greatly increase breast cancer risk encode for proteins that converge on a homology-directed DNA damage repair process. Mutations in the SLX4 gene, which encodes for a scaffold protein involved in the repair of interstrand cross-links, have recently been identified in unclassified Fanconi anemia patients. A mutation analysis of SLX4 in German or Byelorussian familial cases of breast cancer without detected mutations in BRCA1 or BRCA2 has been completed, with globally negative results. 
Methods: The genomic region of SLX4, comprising all exons and exon-intron boundaries, was sequenced in 94 Spanish familial breast cancer cases that match a criterion indicating the potential presence of a highly-penetrant germline mutation, following exclusion of BRCA1 or BRCA2 mutations. 
Results: This mutational analysis revealed extensive genetic variation of SLX4, with 21 novel single nucleotide variants; however, none could be linked to a clear alteration of the protein function. Nonetheless, genotyping 10 variants (nine novel, all missense amino acid changes) in a set of controls (138 women and 146 men) did not detect seven of them. Conclusions: Overall, while the results of this study do not identify clearly pathogenic mutations of SLX4 contributing to breast cancer risk, further genetic analysis, combined with functional assays of the identified rare variants, may be warranted to conclusively assess the potential link with the disease.
KW  - SLX4
KW  - Holliday junction reolvass
KW  - Fanconi-anemia subtype
KW  - susceptibility gene
KW  - helicase BRIP1
KW  - ovarian cancer
KW  - DNA repair
KW  - mutations
KW  - protein
KW  - RAD51C
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131772
VL  - 12
IS  - 84
ER  -