Circulating human B lymphocytes are deficient in nucleotide excision repair and accumulate mutations upon proliferation

Hyka-Nouspikel, Nevila and Lemonidis, Kimon and Lu, Wei-Ting and Nouspikel, Thierry (2011) Circulating human B lymphocytes are deficient in nucleotide excision repair and accumulate mutations upon proliferation. Blood. pp. 6277-6286. ISSN 0006-4971 (https://doi.org/10.1182/blood-2010-12-326637)

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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.

ORCID iDs

Hyka-Nouspikel, Nevila, Lemonidis, Kimon ORCID logoORCID: https://orcid.org/0000-0003-1332-6002, Lu, Wei-Ting and Nouspikel, Thierry;
CORE (COnnecting REpositories)