title: Defective replication stress response inhibits lymphomagenesis and impairs lymphocyte reconstitution.
abstract: DNA replication stress promotes genome instability in cancer. However, the contribution of the replication stress response to the development of malignancies remains unresolved. The DNA replication stress response protein SMARCAL1 stabilizes DNA replication forks and prevents replication fork collapse, a cause of DNA breaks and apoptosis. While the fork regression/remodeling functions of SMARCAL1 have been investigated, its in vivo functions in replication stress and cancer are unclear. Using a gamma radiation (IR)-induced replication stress T-cell lymphoma mouse model, we observed a significant inhibition of lymphomagenesis in mice lacking one or both alleles of Smarcal1. Notably, a quarter of the Smarcal1-deficient mice did not develop tumors. Moreover, hematopoietic stem/progenitor cells (HSPCs) and developing thymocytes in Smarcal1-deficient mice showed increased DNA damage and apoptosis during the proliferation burst following IR and an impaired ability to repopulate the thymus after IR. Additionally, mice lacking Smarcal1 showed significant HSPC defects when challenged to respond to other replication stress stimuli. Thus, our data reveal the critical function of the DNA replication stress response and, specifically, Smarcal1 in hematopoietic cell survival and tumor development. Our results also provide important insight into the immunodeficiency observed in individuals with mutations in SMARCAL1 by suggesting that it is an HSPC defect.
authors: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors: M V
authors: MV
authors: Puccetti
authors: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: M A
authors: MA
authors: Fischer
authors: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: M P
authors: MP
authors: Arrate
authors: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: K L
authors: KL
authors: Boyd
authors: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: R J
authors: RJ
authors: Duszynski
authors: Department of Biochemistry, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: R
authors: R
authors: Bétous
authors: Department of Biochemistry, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: D
authors: D
authors: Cortez
authors: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors: C M
authors: CM
authors: Eischen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics / Q000528:radiation effects; D004249:DNA Damage / Q000235:genetics / Q000528:radiation effects; D004265:DNA Helicases / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics / Q000528:radiation effects; D004277:DNA, Single-Stranded / Q000528:radiation effects; D004195:Disease Models, Animal; D005720:Gamma Rays; D042822:Genomic Instability / Q000235:genetics* / Q000528:radiation effects; D006412:Hematopoietic Stem Cells / Q000473:pathology; D006801:Humans; D008214:Lymphocytes / Q000473:pathology / Q000528:radiation effects; D016399:Lymphoma, T-Cell / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009154:Mutation
chemical_list: D004277:DNA, Single-Stranded; C412482:SMARCAL1 protein, human; C485869:Smarcal1 protein, mouse; D004265:DNA Helicases