FANCD2 Alleviates Physiologic Replication Stress in Fetal Liver HSC
Preprint posted on October 01, 2020 https://www.biorxiv.org/content/10.1101/2020.09.30.320796v1?ct=
In proliferating hematopoietic stem cells, FA proteins keep replication stress at bay.
Selected by RamCategories: cell biology, developmental biology, molecular biology, physiology
Background
Fanconi Anemia (FA) pathway constituting 22 genes supports cellular DNA damage response during replication stress. Biallelic germline mutations in FA pathway genes cause FA (the most frequent bone marrow failure syndrome), predisposes individuals to different cancers and incurs anomalies in the hematopoietic stem cell (HSC) compartment, all of which attributed to DNA damage accumulation and sensitivity to DNA damaging agents1. In adults, HSCs are maintained in quiescence for a future activation to match the demand of blood cell lineages. While many studies reinforce the importance of the FA pathway proteins to thwart exogenous sources of replication stress, it is not clear what physiological role FA pathway proteins play to maintain the integrity of the HSC pool. Therefore, the authors of the current preprint set out to investigate this.
Key findings
- The authors first demonstrate that HSCs derived from Fancd2-/- (a FA gene) show functional deficits in a later stage of mouse development (after E12.5) compared to wild-type. Furthermore, to resolve the precise cell cycle deficiencies often observed in Fancd2-/-, the authors exploit a sequential double stain of EdU followed by BrdU to segregate HSC pool that are in different cell cycle stages: G2/M (EdU+), S (EdU+/BrdU+), and entering S (BrdU+) (fig. a). Based on this data, they suggest that fetal liver HSCs derived from Fancd2-/- mice manifest delayed S-phase entry or progression, albeit they are not quiescent as well.
- As Fancd2-/- increases susceptibility to DNA damaging agents, the authors tested if lack of Fancd2 would inherently induce replication stress leading to the delayed S-phase entry they observed earlier. To this end, they detected higher levels of replication stress markers like phosphorylated Replication protein A (pRPA32 S4/S8), phosphorylated Checkpoint kinase 1 (pChk1 S345), and phosphorylated Minichromosome Maintenance complex (pMcm2 S53/S108) in fetal liver HSCs derived from Fancd2-/-.
- They further demonstrated exaggerated Cdkn1a (also called p21) nuclear localization in fetal liver HSCs derived from Fancd2-/- (fig. b), suggestive of p53-independent activation of cell cycle delay. Interestingly, chemical inhibition (SD208) of TGF-β (a key signaling molecule in HSC) was sufficient to reverse p21 nuclear localization, reinforcing a p53-independent activation of cell cycle delay.
(a) Kinetic cell cycles studies adapting a sequential EdU/BrdU injection protocol with sequential EdU/BrdU injection at E13.5, (b) Immunofluorescence of Cdkn1a(p21) (WT n=4 pups, 84 cells, Fancd2-/-; n=4 pups, 120 cells), (c) Molecular mechanism of replication stress-mediated HSC integrity in Fancd2-/-. Taken directly from Muchizuki-Kashio M et. al., 2020 under a CC-BY 4.0 international license.
Conclusion
The authors report a physiologic role for Fancd2 to counter endogenous replication stress in proliferating HSCs in vivo, a mechanism challenged in FA individuals (fig. c). They further report that Fancd2 supports rapidly proliferating HSCs in the fetal liver to sustain lifelong HSC supply.
Acknowledgments: Thanks to all the authors, especially Makiko Mochizuki-Kashio and Peter Kurre for openly sharing unpublished data and replying promptly.
References:
- https://doi.org/10.1016/j.cub.2017.07.043
- https://dx.doi.org/10.1016%2Fj.stemcr.2016.09.005
- https://doi.org/10.1038/s41467-019-12271-w
- https://doi.org/10.1371/journal.pgen.1005674
- https://doi.org/10.1016/j.molcel.2015.09.012
Posted on: 14th October 2020
doi: https://doi.org/10.1242/prelights.25076
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