title: Circulating human B lymphocytes are deficient in nucleotide excision repair and accumulate mutations upon proliferation.
abstract: Faithful repair of DNA lesions is a crucial task that dividing cells must actively perform to maintain genome integrity. Strikingly, nucleotide excision repair (NER), the most versatile DNA repair system, is specifically down-regulated in terminally differentiated cells. This prompted us to examine whether NER attenuation might be a common feature of all G₀-arrested cells, and in particular of those that retain the capacity to reenter cell cycle and might thus convert unrepaired DNA lesions into mutations, a prerequisite for malignant transformation. Here we report that quiescent primary human B lymphocytes down-regulate NER at the global genome level while maintaining proficient repair of constitutively expressed genes. Quiescent B cells exposed to an environment that causes both DNA damage and proliferation accumulate point mutations in silent and inducible genes crucial for cell replication and differentiation, such as BCL6 and Cyclin D2. Similar to differentiated cells, NER attenuation in quiescent cells is associated with incomplete phosphorylation of the ubiquitin activating enzyme Ube1, which is required for proficient NER. Our data establish a mechanistic link between NER attenuation during quiescence and cell mutagenesis and also support the concept that oncogenic events targeting cell cycle- or activation-induced genes might initiate genomic instability and lymphomagenesis.
authors.affiliation: Institute for Cancer Studies, University of Sheffield, Sheffield, UK.
authors.forename: Nevila
authors.initials: N
authors.lastname: Hyka-Nouspikel
authors.forename: Kimon
authors.initials: K
authors.lastname: Lemonidis
authors.forename: Wei-Ting
authors.initials: WT
authors.lastname: Lu
authors.forename: Thierry
authors.initials: T
authors.lastname: Nouspikel
mesh_terms: D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D056742:Cyclin D2 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics*; D015894:Genome, Human; D042822:Genomic Instability; D006801:Humans; D016296:Mutagenesis; D009154:Mutation; D051560:Proto-Oncogene Proteins c-bcl-6; D016192:Resting Phase, Cell Cycle / Q000235:genetics*; D044764:Ubiquitin-Activating Enzymes
chemical_list: C084103:BCL6 protein, human; C080336:CCND2 protein, human; D056742:Cyclin D2; D004268:DNA-Binding Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; C471538:UBA1 protein, human; D044764:Ubiquitin-Activating Enzymes