title: Nucleotide excision repair and B lymphoma: somatic hypermutation is not the only culprit.
abstract: Different mechanisms account for the development of B lymphoma. Malignant transformation of B lymphocytes arises from progressive loss of genome integrity combined with uncontrolled cell proliferation, often triggered by foreign or self antigens. It is well established that somatic hypermutation, the pathway responsible for introducing high levels of mutations in immunoglobulin genes, also targets several other genes, contributing mainly to germinal center-derived B-cell lymphoma. We have recently discovered that a major DNA repair pathway, nucleotide excision repair (NER), is downregulated in quiescent B lymphocytes. Upon B-cell stimulation, unrepaired DNA damage results in the accumulation of mutations in a different and likely larger set of genes, including normally silent genes (e.g., oncogenes) as well as cell cycle and activation-induced genes. This mechanism potentially produces a transforming event relevant to a wider palette of B lymphomas. Here we discuss the relative contribution of both mechanisms to lymphomagenesis and possible implications of NER downregulation for other types of malignancies and for B cell-mediated immunity. Given that hematopoietic cancer stem cells remain quiescent for long periods of time, we propose that downregulation of NER during quiescence, in an environment that causes both genotoxic stress and proliferation, could be a general mechanism for carcinogenesis.
authors.affiliation: Institute for Cancer Studies, University of Sheffield, Sheffield, UK.
authors.forename: Nevila
authors.initials: N
authors.lastname: Hyka-Nouspikel
authors.forename: Thierry
authors.initials: T
authors.lastname: Nouspikel
mesh_terms: D004249:DNA Damage; D004260:DNA Repair; D018858:Germinal Center; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000378:metabolism; D010766:Phosphorylation; D051758:Transcription Factor TFIIH / Q000378:metabolism; D044764:Ubiquitin-Activating Enzymes / Q000378:metabolism; D014452:Ubiquitins / Q000378:metabolism
chemical_list: C471538:UBA1 protein, human; D014452:Ubiquitins; D051758:Transcription Factor TFIIH; D044764:Ubiquitin-Activating Enzymes