RESUMO
DNA repair is essential for maintaining genomic stability, and defects in this process significantly increase the risk of cancer. Clear-cell renal cell carcinoma (CCRCC) caused by inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is characterized by high genomic instability. However, the molecular mechanism underlying the association between the loss of VHL and genomic instability remains unclear. Here, we show that suppressor of cytokine signaling 1 (SOCS1) promotes nuclear redistribution and K63-ubiquitylation of VHL in response to DNA double-strand breaks (DSBs). Loss of VHL or VHL mutations that compromise its K63-ubiquitylation attenuates the DNA-damage response (DDR), resulting in decreased homologous recombination repair and persistence of DSBs. These results identify VHL as a component of the DDR network, inactivation of which contributes to the genomic instability associated with CCRCC.
Assuntos
Dano ao DNA , Reparo do DNA , DNA/genética , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo , Humanos , Lisina/química , Lisina/metabolismo , Proteína 1 Supressora da Sinalização de Citocina , Ubiquitinação , Proteína Supressora de Tumor Von Hippel-Lindau/química , Proteína Supressora de Tumor Von Hippel-Lindau/genéticaRESUMO
TCL1 is an oncogene activated by recurrent reciprocal translocations at chromosome segment 14q32.1 in the most common of the mature T-cell malignancies, T-cell prolymphocytic leukemia. It acts to transport Akt1 to the nucleus and enhance Akt1's serine-threonine kinase activity. TCL1 is also expressed in the B-cell malignancy, Burkitt's lymphoma (BL). However, 14q32.1 breakpoints have not been detected in BL, and we therefore investigated in more detail how expression was activated. No evidence for rearrangement near TCL1 was found in BL. Instead, a NotI site adjacent to the TATA box in the TCL1 promoter was found to be unmethylated. By contrast, tumor cell lines not expressing TCL1 were fully methylated at this NotI site, while normal somatic cells were hemimethylated. We also found that TCL1 was expressed in B-cell chronic lymphocytic leukemia (CLL) and the related disorder splenic lymphoma with villous lymphocytes (unlike in normal mature B-cells), and that the NotI site was unmethylated on both alleles. This correlation of repression and methylation was tested in vitro. When cells with both alleles methylated at the NotI site were demethylated, TCL1 expression was induced. These data provide evidence that in mature B-cell malignancies there is an alternative mechanism of TCL1 activation that apparently involves loss of methylation of one promoter allele. We discuss the significance of this for CLL tumorigenesis and for genomewide hypomethylation in CLL.
Assuntos
Cromossomos Humanos Par 14/genética , Metilação de DNA , Regulação Neoplásica da Expressão Gênica/genética , Rearranjo Gênico/genética , Genes Neoplásicos , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Sequência de Bases , Células HT29 , Humanos , Células Jurkat , Dados de Sequência Molecular , Proteínas Proto-Oncogênicas/biossíntese , Células Tumorais CultivadasRESUMO
T cell prolymphocytic leukaemia (T-PLL) is a chronic mature T cell malignancy with many random cytogenetic abnormalities. These imply that maintenance of genomic integrity is impaired. This is supported by the recent finding that the ataxia telangiectasia gene, ATM, which contributes to maintaining genomic integrity, is frequently mutated in this disease. To evaluate in T-PLL the role of other genes with comparable function, a fluorescence-based semi-automated assay was developed for BAT-25 and BAT-26. These markers contain sequences that are particularly unstable in cells with DNA mismatch repair defects. Application of the assay to 20 T-PLL cases found no evidence for such defects.
Assuntos
Reparo do DNA/genética , Leucemia Prolinfocítica de Células T/genética , Leucemia Prolinfocítica/genética , Fluorescência , Humanos , Poli ARESUMO
Bcl10 is a cancer gene recently identified in B-cell lymphomas of mucosa-associated lymphoid tissues. It has been suggested as a target for mutation in multiple types of tumour including follicular lymphoma, T-cell acute lymphoblastic leukaemia and Sezary syndrome. To evaluate further the role of Bcl10 in human adult haematological cancers, we screened for mutations samples from 24 patients with B-cell chronic lymphocytic leukaemia (CLL) and 18 samples from patients with T-cell prolymphocytic leukaemia (T-PLL). No pathogenic mutations were detected in any of the samples analysed, strongly suggesting that Bcl10 is not involved in the development of CLL or T-PLL and that its involvement may be restricted to other haematological malignancies.
