DNA Damage Response in Hematopoietic Stem Cell Ageing

Maintenance of tissue-specific stem cells is vital for organ homeostasis and organismal longevity.Hematopoietic stem cells（HSCs） are the most primitive cell type in the hematopoietic system.They divide asymmetrically and give rise to daughter cells with HSC identity（selfrenewal） and progenitor progenies（differentiation）,which further proliferate and differentiate into full hematopoietic lineages.Mammalian ageing process is accompanied with abnormalities in the HSC self-renewal and differentiation.Transcriptional changes and epigenetic modulations have been implicated as the key regulators in HSC ageing process.The DNA damage response（DDR）in the cells involves an orchestrated signaling pathway,consisting of cell cycle regulation,cell death and senescence,transcriptional regulation,as well as chromatin remodeling.Recent studies employing DNA repair-deficient mouse models indicate that DDR could intrinsically and extrinsically regulate HSC maintenance and play important roles in tissue homeostasis of the hematopoietic system.In this review,we summarize the current understanding of how the DDR determines the HSC fates and finally contributes to organismal ageing.

Gadd45a deletion aggravates hematopoietic stem cell dysfunction in ATM-deficient mice

Ataxia telangiectasia mutated （ATM） kinase plays an essential role in the maintenance of genomic stability. ATM-deficient （ATM-/-） mice exhibit hematopoietic stem cell （HSC） dysfunction and a high incidence of lym- phoma. Gadd45a controls cell cycle arrest, apoptosis and DNA repair, and is involved in the ATM-p53 mediated DNA damage response. However, the role of Gadd45a in regulating the functionality of ATM-/- HSCs is unknown. Here we report that Gadd45a deletion did not rescue the defects of T-cells and B-cells development in ATM-/- mice. Instead, ATM and Gadd45a double knockout （ATM-/- Gadd45a-/-） HSCs exhibited an aggravated defect in long-term self-renewal capacity compared to ATM-/- HSCs in HSC transplantation experiments. Fur- ther experiments revealed that the aggravated defect of ATM-/- Gadd45a-/- HSCs was due to a reduction of cell proliferation, associated with an accumulation of DNA damage and subsequent activation of DNA damage response including an up-regulation of p53-p21 signal- ing pathway. Additionally, ATM-/- Gadd45a-/- mice showed an increased incidence of hematopoietic malignancies, as well as an increased rate of metastasis than ATM-/- mice. In conclusion, Gadd45a deletion aggravated the DNA damage accumulation, which sub- sequently resulted in a further impaired self-renewal capacity and an increased malignant transformation in ATM-/- HSCs.