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

Nevila Hyka-Nouspikel, Kimon Lemonidis, Wei-Ting Lu and Thierry Nouspikel


Faithful repair of DNA lesions is a crucial task that dividing cells must actively carry out to maintain genome integrity. Strikingly, nucleotide excision repair (NER), the most versatile DNA repair system, is specifically downregulated 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 re-enter 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 downregulate 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 BCL-6 and Cyclin D2. Similarly 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 support the concept that oncogenic events targeting cell cycle- or activation-induced genes might initiate genomic instability and lymphomagenesis.

  • Submitted December 22, 2010.
  • Accepted April 4, 2011.