Lymphocyte lineage-specific and developmental stage specific mechanisms suppress cyclin D3 expression in response to DNA double strand breaks.
Mammalian cells are thought to protect themselves and their host organisms from DNA double strand breaks (DSBs) through universal mechanisms that restrain cellular proliferation until DNA is repaired. The Cyclin D3 protein drives G1-to-S cell cycle progression and is required for proliferation of immature T and B cells and of mature B cells during a T cell-dependent immune response. We demonstrate that mouse thymocytes and pre-B cells, but not mature B cells, repress Cyclin D3 protein levels in response to DSBs. This response requires the ATM protein kinase that is activated by DSBs. Cyclin D3 protein loss in thymocytes coincides with decreased association of Cyclin D3 mRNA with the HuR RNA binding protein that ATM regulates. HuR inactivation reduces basal Cyclin D3 protein levels without affecting Cyclin D3 mRNA levels, indicating that thymocytes repress Cyclin D3 expression via ATM-dependent inhibition of Cyclin D3 mRNA translation. In contrast, ATM-dependent transcriptional repression of the Cyclin D3 gene represses Cyclin D3 protein levels in pre-B cells. Retrovirus-driven Cyclin D3 expression is resistant to transcriptional repression by DSBs; this prevents pre-B cells from suppressing Cyclin D3 protein levels and from inhibiting DNA synthesis to the normal extent following DSBs. Our data indicate that immature B and T cells use lymphocyte lineage- and developmental stage-specific mechanisms to inhibit Cyclin D3 protein levels and thereby help prevent cellular proliferation in response to DSBs. We discuss the relevance of these cellular context-dependent DSB response mechanisms in restraining proliferation, maintaining genomic integrity, and suppressing malignant transformation of lymphocytes.
a Division of Cancer Pathobiology, Department of Pathology and Laboratory Medicine , Center for Childhood Cancer Research, Children's Hospital of Philadelphia , Philadelphia , PA , USA.|b Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania , Philadelphia , PA , USA.
Amy
A
DeMicco
a Division of Cancer Pathobiology, Department of Pathology and Laboratory Medicine , Center for Childhood Cancer Research, Children's Hospital of Philadelphia , Philadelphia , PA , USA.
Tyler
T
Reich
a Division of Cancer Pathobiology, Department of Pathology and Laboratory Medicine , Center for Childhood Cancer Research, Children's Hospital of Philadelphia , Philadelphia , PA , USA.
Rahul
R
Arya
a Division of Cancer Pathobiology, Department of Pathology and Laboratory Medicine , Center for Childhood Cancer Research, Children's Hospital of Philadelphia , Philadelphia , PA , USA.|b Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania , Philadelphia , PA , USA.
Adrian
A
Rivera-Reyes
a Division of Cancer Pathobiology, Department of Pathology and Laboratory Medicine , Center for Childhood Cancer Research, Children's Hospital of Philadelphia , Philadelphia , PA , USA.|c Immunology Graduate Group, Perelman School of Medicine at the University of Pennsylvania , Philadelphia , PA , USA.
Megan R
MR
Fisher
a Division of Cancer Pathobiology, Department of Pathology and Laboratory Medicine , Center for Childhood Cancer Research, Children's Hospital of Philadelphia , Philadelphia , PA , USA.|b Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania , Philadelphia , PA , USA.|c Immunology Graduate Group, Perelman School of Medicine at the University of Pennsylvania , Philadelphia , PA , USA.|d Department of Pathology and Laboratory Medicine , Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania , Philadelphia , PA , USA.
Craig H
CH
Bassing
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology / Q000528:radiation effects; D019070:Cell Lineage / Q000235:genetics / Q000528:radiation effects; D049109:Cell Proliferation / Q000528:radiation effects; D056743:Cyclin D3 / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D015536:Down-Regulation / Q000528:radiation effects; D000067780:ELAV-Like Protein 1 / Q000378:metabolism; D048788:Growth and Development / Q000235:genetics; D008214:Lymphocytes / Q000166:cytology*; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011839:Radiation, Ionizing; D012190:Retroviridae / Q000378:metabolism; D015398:Signal Transduction / Q000528:radiation effects; D013379:Substrate Specificity / Q000528:radiation effects; D013601:T-Lymphocytes / Q000166:cytology / Q000528:radiation effects; D014158:Transcription, Genetic / Q000528:radiation effects
D056743:Cyclin D3; D000067780:ELAV-Like Protein 1; D012333:RNA, Messenger; D004247:DNA; D064007:Ataxia Telangiectasia Mutated Proteins
ATM; Cyclin D3; DNA damage response; HuR; lymphocytes