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  - Galetzka, Danuta
A1  - Hansmann, Tamara
A1  - El Hajj, Nady
A1  - Weis, Eva
A1  - Irmscher, Benjamin
A1  - Ludwig, Marco
A1  - Schneider-Rätzke, Brigitte
A1  - Kohlschmidt, Nicolai
A1  - Beyer, Vera
A1  - Bartsch, Oliver
A1  - Zechner, Ulrich
A1  - Spix, Claudia
A1  - Haaf, Thomas
T1  - Monozygotic twins discordant for constitutive BRCA1 promoter methylation, childhood cancer and secondary cancer
JF  - Epigenetics
N2  - We describe monozygotic twins discordant for childhood leukemia and secondary thyroid carcinoma. We used bisulfite pyrosequencing to compare the constitutive promoter methylation of BRCA1 and several other tumor suppressor genes in primary fibroblasts. The affected twin displayed an increased BRCA1 methylation (12%), compared with her sister (3%). Subsequent bisulfite plasmid sequencing demonstrated that 13% (6 of 47) BRCA1 alleles were fully methylated in the affected twin, whereas her sister displayed only single CpG errors without functional implications. This between-twin methylation difference was also found in irradiated fibroblasts and untreated saliva cells. The BRCA1 epimutation may have originated by an early somatic event in the affected twin: approximately 25% of her body cells derived from different embryonic cell lineages carry one epigenetically inactivated BRCA1 allele. This epimutation was associated with reduced basal protein levels and a higher induction of BRCA1 after DNA damage. In addition, we performed a genome-wide microarray analysis of both sisters and found several copy number variations, i.e., heterozygous deletion and reduced expression of the RSPO3 gene in the affected twin. This monozygotic twin pair represents an impressive example of epigenetic somatic mosaicism, suggesting a role for constitutive epimutations, maybe along with de novo genetic alterations in recurrent tumor development.
KW  - BRCA1
KW  - childhood cancer
KW  - DNA Methylation
KW  - epimutation
KW  - monozygotic twins
KW  - secondary cancer
KW  - somatic mosaicism
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125386
VL  - 7
IS  - 1
ER  -