title: Xpg limits the expansion of haematopoietic stem and progenitor cells after ionising radiation.
abstract: Reduced capacity of genome maintenance represents a problem for any organism, potentially causing premature death, carcinogenesis, or accelerated ageing. Strikingly though, loss of certain genome stability factors can be beneficial, especially for the maintenance of tissue stem cells of the intestine and the haematopoietic system. We therefore screened for genome stability factors negatively impacting maintenance of haematopoietic stem cells (HSC) in the context of ionising radiation (IR). We found that in vivo knock down of Xeroderma pigmentosum, complementation group G (Xpg) causes elevation of HSC numbers after IR treatment, while numbers of haematopoietic progenitors are elevated to a lesser extent. IR rapidly induces Xpg both on mRNA and on protein level. Prevention of this induction does not influence activation of the checkpoint cascade, yet attenuates late checkpoint steps such as induction of p21 and Noxa. This causes a leaky cell cycle arrest and lower levels of apoptosis, both contributing to increased colony formation and transformation rates. Xpg thus helps to adequately induce DNA damage responses after IR, thereby keeping the expansion of damaged cells under control. This represents a new function of Xpg in the response to IR, in addition to its well-characterized role in nucleotide excision repair.
authors.affiliation: Leibniz Institute on Aging, Fritz Lipmann Institute, 07745 Jena, Germany.
authors.forename: Alush I
authors.initials: AI
authors.lastname: Avila
authors.affiliation: Department of Internal Medicine I, Ulm University, 89081 Ulm, Germany.
authors.forename: Anett
authors.initials: A
authors.lastname: Illing
authors.affiliation: Leibniz Institute on Aging, Fritz Lipmann Institute, 07745 Jena, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Becker
authors.affiliation: Institute for Biochemistry and Molecular Biology, Ulm University, 89081 Ulm, Germany.
authors.forename: Lars D
authors.initials: LD
authors.lastname: Maerz
authors.affiliation: Leibniz Institute on Aging, Fritz Lipmann Institute, 07745 Jena, Germany.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Morita
authors.affiliation: Institute for Biochemistry and Molecular Biology, Ulm University, 89081 Ulm, Germany.
authors.forename: Melanie
authors.identifier: 0000-0003-2714-965X
authors.initials: M
authors.lastname: Philipp
authors.affiliation: Leibniz Institute on Aging, Fritz Lipmann Institute, 07745 Jena, Germany Institute for Biochemistry and Molecular Biology, Ulm University, 89081 Ulm, Germany martin.burkhalter@uni-ulm.de.
authors.forename: Martin D
authors.initials: MD
authors.lastname: Burkhalter
mesh_terms: D017209:Apoptosis / Q000528:radiation effects; D063646:Carcinogenesis / Q000528:radiation effects*; D059447:Cell Cycle Checkpoints / Q000528:radiation effects; D004249:DNA Damage / Q000528:radiation effects; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D004720:Endonucleases / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000528:radiation effects; D055785:Gene Knockdown Techniques; D042822:Genomic Instability / Q000187:drug effects* / Q000528:radiation effects; D006412:Hematopoietic Stem Cells / Q000528:radiation effects*; D006801:Humans; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D011839:Radiation, Ionizing; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014983:Xeroderma Pigmentosum / Q000235:genetics; D000099250:DNA Excision Repair Protein ERCC-5
chemical_list: D004268:DNA-Binding Proteins; D004720:Endonucleases; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D000099250:DNA Excision Repair Protein ERCC-5