10:30 AM on Friday, November 1, 2013
Location: VTRC - Arlington; 4-024; 900, N Glebe Rd, Arlington, VA 22203
Invited Speaker: Dr. Robert Babak Faryabi, NIH (Laboratory of Genome Integrity, National Cancer Institute)
DNA double strand breaks (DSBs) in B lymphocytes are thought to arise stochastically during S phase or as a result of targeted DNA damage by activation induced cytidine deaminase (AID) in G1. Lymphocytes are susceptible to replication-stress-inducing agents such as hydroxyurea (HU) since they undergo rapid after their activation. Using genome-wide profiling of DNA repair proteins RPA, SMC5, γ-H2AX, and BRCA1 in primary murine lymphocytes treated with HU, we identify a novel class of recurrent DNA lesions at early replicating sites, termed Early Replication Fragile Sites (ERFS). RFSs colocalize preferentially with highly expressed gene clusters, particularly with regions of active divergent or convergent transcription. ERFSs are also enriched for repetitive elements and CpG dinucleotides, which are frequently found at translocation breakpoints in B cell lymphomas. Metaphase analysis shows that ERFSs break in response to replication stress and deregulated expression of the oncogene c-Myc. ERFSs also translocate to AID-induced breaks at the Immunoglobulin Heavy chain gene. Moreover, greater than 50% of common copy number variations observed in human diffuse large B cell lymphoma map to ERFS. Interestingly, genes rearranged frequently in B cell lymphoma such as IKZF1, BACH2 and BCL2 are located within the strongest identified ERFS. In summary, we have identified a new class of fragile sites in mammalian cells, which play a mechanistic role in recurrent rearrangements during lymphomagenesis.