title: Endogenous DNA Damage Leads to p53-Independent Deficits in Replicative Fitness in Fetal Murine Fancd2-/-Hematopoietic Stem and Progenitor Cells.
abstract: Our mechanistic understanding of Fanconi anemia (FA) pathway function in hematopoietic stem and progenitor cells (HSPCs) owes much to their role in experimentally induced DNA crosslink lesion repair. In bone marrow HSPCs, unresolved stress confers p53-dependent apoptosis and progressive cell attrition. The role of FA proteins during hematopoietic development, in the face of physiological replicative demand, remains elusive. Here, we reveal a fetal HSPC pool in Fancd2-/-mice with compromised clonogenicity and repopulation. Without experimental manipulation, fetal Fancd2-/-HSPCs spontaneously accumulate DNA strand breaks and RAD51 foci, associated with a broad transcriptional DNA-damage response, and constitutive activation of ATM as well as p38 stress kinase. Remarkably, the unresolved stress during rapid HSPC pool expansion does not trigger p53 activation and apoptosis; rather, it constrains proliferation. Collectively our studies point to a role for the FA pathway during hematopoietic development and provide a new model for studying the physiological function of FA proteins.
authors.affiliation: Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA; Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR 97239, USA; Pediatric Cancer Biology Program, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Young Me
authors.initials: YM
authors.lastname: Yoon
authors.affiliation: Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA; Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR 97239, USA; Pediatric Cancer Biology Program, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Kelsie J
authors.initials: KJ
authors.lastname: Storm
authors.affiliation: Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA; Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR 97239, USA; Pediatric Cancer Biology Program, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Ashley N
authors.initials: AN
authors.lastname: Kamimae-Lanning
authors.affiliation: Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA; Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR 97239, USA; Pediatric Cancer Biology Program, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Natalya A
authors.initials: NA
authors.lastname: Goloviznina
authors.affiliation: Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA; Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR 97239, USA; Pediatric Cancer Biology Program, Oregon Health & Science University, Portland, OR 97239, USA; OHSU Knight Cancer Institute, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA. Electronic address: kurrepe@ohsu.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Kurre
mesh_terms: D000818:Animals; D017209:Apoptosis; D016207:Cytokines / Q000378:metabolism; D053960:DNA Breaks / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004261:DNA Replication; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics*; D005333:Fetus; D056084:Genetic Fitness; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D013312:Stress, Physiological / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016207:Cytokines; D052236:Fanconi Anemia Complementation Group D2 Protein; D016159:Tumor Suppressor Protein p53; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Fanconi anemia; bone marrow failure; development; hematopoiesis; stem cells