DNA damage defines sites of recurrent chromosomal translocations in B lymphocytes.
Recurrent chromosomal translocations underlie both haematopoietic and solid tumours. Their origin has been ascribed to selection of random rearrangements, targeted DNA damage, or frequent nuclear interactions between translocation partners; however, the relative contribution of each of these elements has not been measured directly or on a large scale. Here we examine the role of nuclear architecture and frequency of DNA damage in the genesis of chromosomal translocations by measuring these parameters simultaneously in cultured mouse B lymphocytes. In the absence of recurrent DNA damage, translocations between Igh or Myc and all other genes are directly related to their contact frequency. Conversely, translocations associated with recurrent site-directed DNA damage are proportional to the rate of DNA break formation, as measured by replication protein A accumulation at the site of damage. Thus, non-targeted rearrangements reflect nuclear organization whereas DNA break formation governs the location and frequency of recurrent translocations, including those driving B-cell malignancies.
Laboratory of Receptor Biology and Gene Expression, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA.
Ofir
O
Hakim
Wolfgang
W
Resch
Arito
A
Yamane
Isaac
I
Klein
Kyong-Rim
KR
Kieffer-Kwon
Mila
M
Jankovic
Thiago
T
Oliveira
Anne
A
Bothmer
Ty C
TC
Voss
Camilo
C
Ansarah-Sobrinho
Ewy
E
Mathe
Genqing
G
Liang
Jesse
J
Cobell
Hirotaka
H
Nakahashi
Davide F
DF
Robbiani
Andre
A
Nussenzweig
Gordon L
GL
Hager
Michel C
MC
Nussenzweig
Rafael
R
Casellas
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism* / Q000473:pathology*; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D045584:Chromosome Positioning; D033481:Chromosomes, Mammalian / Q000235:genetics / Q000378:metabolism; D003564:Cytidine Deaminase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000235:genetics*; D016259:Genes, myc / Q000235:genetics; D016678:Genome / Q000235:genetics; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D051379:Mice; D051716:Replication Protein A / Q000378:metabolism; D014178:Translocation, Genetic / Q000235:genetics*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D007143:Immunoglobulin Heavy Chains; D051716:Replication Protein A; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase