DNA double-strand breaks activate a multi-functional genetic program in developing lymphocytes.
DNA double-strand breaks are generated by genotoxic agents and by cellular endonucleases as intermediates of several important physiological processes. The cellular response to genotoxic DNA breaks includes the activation of transcriptional programs known primarily to regulate cell-cycle checkpoints and cell survival. DNA double-strand breaks are generated in all developing lymphocytes during the assembly of antigen receptor genes, a process that is essential for normal lymphocyte development. Here we show that in murine lymphocytes these physiological DNA breaks activate a broad transcriptional program. This program transcends the canonical DNA double-strand break response and includes many genes that regulate diverse cellular processes important for lymphocyte development. Moreover, the expression of several of these genes is regulated similarly in response to genotoxic DNA damage. Thus, physiological DNA double-strand breaks provide cues that can regulate cell-type-specific processes not directly involved in maintaining the integrity of the genome, and genotoxic DNA breaks could disrupt normal cellular functions by corrupting these processes.
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Andrea L
AL
Bredemeyer
Beth A
BA
Helmink
Cynthia L
CL
Innes
Boris
B
Calderon
Lisa M
LM
McGinnis
Grace K
GK
Mahowald
Eric J
EJ
Gapud
Laura M
LM
Walker
Jennifer B
JB
Collins
Brian K
BK
Weaver
Laura
L
Mandik-Nayak
Robert D
RD
Schreiber
Paul M
PM
Allen
Michael J
MJ
May
Richard S
RS
Paules
Craig H
CH
Bassing
Barry P
BP
Sleckman
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000187:drug effects; D002460:Cell Line; D053903:DNA Breaks, Double-Stranded; D004268:DNA-Binding Proteins / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics*; D018398:Homeodomain Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000187:drug effects
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D018398:Homeodomain Proteins; D016328:NF-kappa B; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases