English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

Background  Recent studies have shown that deficiency in the Fanconi anemia (FA) DNA repair pathway enhances the error-prone non-homologous end-joining (NHEJ) repair, leading to increased genomic instability, and that genetic or pharmacological inhibition of the NHEJ pathway could rescue the FA phenotype.    Methods  First, we exposed LSK cells from WT and  Fanca   −/−   mice to DNA-PKcs inhibitor NU7026 or Ku70 knockdown to examine whether inhibition of NHEJ sensitizes  Fanca   −/−   HSPCs to PARP inhibitor (PARPi)- or interstrand crosslinking (ICL)-induced cell death and genomic instability. We then generated  DNA-PKcs   3A/3A   Fanca   −/−   mice to investigate the effect of specific inactivation of NHEJ on fetal HSCs. Lastly, we used two p53 mutant models to test whether specific inactivation of the p53 function in apoptosis is sufficient to rescue embryonic lethality and fetal HSC depletion in  Fanca   −/−    DNA-PKcs   3A/3A   mice.    Results  Inhibition of NHEJ sensitizes HSPCs from  Fanca   −/−   mice to PARP inhibition- and ICL-induced cell death and genomic instability and further decreases  Fanca   −/−   HSPC proliferation and hematopoietic repopulation in irradiated transplant recipients. Specific inactivation of NHEJ activity by the knockin  DNA-PKcs   3A/3A   mutation in two FA mouse models,  Fanca   −/−   and  Fancc   −/−  , leads to embryonic lethality.  DNA-PKcs   3A/3A   causes fetal HSC depletion in developing  Fanca   −/−   embryos due to increased HSC apoptosis and cycling. Both p53 −/−  and a knockin  p53   515C   mutation, which selectively impairs the p53 function in apoptosis, can rescue embryonic lethality and fetal HSC depletion in  Fanca   −/−    DNA-PKcs   3A/3A   mice.    Conclusion  These results demonstrate that the NHEJ pathway functions to maintain Fanconi anemia fetal HSCs.

The non-homologous end-joining activity is required for Fanconi anemia fetal HSC maintenance