title: Gadd45a regulates hematopoietic stem cell stress responses in mice.
abstract: Gadd45a has been involved in DNA damage response and in many malignancies, including leukemia. However, the function of Gadd45a in hematopoietic stem cells (HSCs) remains unknown. Here, we reported that Gadd45a-deficient (Gadd45a(-/-)) mice showed a normal hematologic phenotype under homeostatic conditions. However, following 5-fluorouracil treatment, Gadd45a(-/-) HSCs exhibited a faster recovery, associated with an increase in the proliferation rate. Interestingly, young Gadd45a(-/-) HSCs showed enhanced reconstitution ability in serial transplantation. Following ionizing radiation (IR), young Gadd45a(-/-) HSCs exhibited an increased resistance to IR-induced DNA damage, associated with a decrease in the apoptosis rate and delayed DNA repair. The significantly higher level of DNA damage in Gadd45a(-/-) HSCs ultimately promoted B-cell leukemia in further transplanted recipient mice. In old mice, Gadd45a(-/-) HSCs were functionally equal to wild-type HSCs but exhibited more DNA damage accumulation and increased sensitivity to IR than wild-type HSCs. In conclusion, Gadd45a plays a significant role in HSC stress responses. Gadd45a deficiency leads to DNA damage accumulation and impairment in apoptosis after exposure to IR, which increases the susceptibility of leukemogenesis.
authors.affiliation: Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, China;
authors.forename: Yulin
authors.initials: Y
authors.lastname: Chen
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Ma
authors.forename: Meimei
authors.initials: M
authors.lastname: Zhang
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Wang
authors.forename: Changxin
authors.initials: C
authors.lastname: Wang
authors.forename: Hu
authors.initials: H
authors.lastname: Wang
authors.forename: Peng
authors.initials: P
authors.lastname: Guo
authors.forename: Weiping
authors.initials: W
authors.lastname: Yuan
authors.forename: Karl Lenhard
authors.initials: KL
authors.lastname: Rudolph
authors.forename: Qimin
authors.initials: Q
authors.lastname: Zhan
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Ju
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects* / Q000528:radiation effects; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005472:Fluorouracil / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology* / Q000528:radiation effects; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D011839:Radiation, Ionizing; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013312:Stress, Physiological / Q000187:drug effects* / Q000528:radiation effects; D000097642:GADD45 Proteins
chemical_list: D000964:Antimetabolites, Antineoplastic; D018797:Cell Cycle Proteins; D005472:Fluorouracil; D009687:Nuclear Proteins; D012333:RNA, Messenger; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C499072:Gadd45a protein, mouse