Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication




Journal article


Stem Cell Reports

Publication Date





840 - 853


Fanconi anemia, bone marrow failure, development, hematopoiesis, stem cells, Animals, Apoptosis, Cytokines, DNA Breaks, DNA Damage, DNA Replication, Fanconi Anemia Complementation Group D2 Protein, Fetus, Genetic Fitness, Hematopoietic Stem Cells, Liver, Mice, Mice, Knockout, Stress, Physiological, Tumor Suppressor Protein p53, p38 Mitogen-Activated Protein Kinases