title: DNA damage-induced Lok/CHK2 activation compromises germline stem cell self-renewal and lineage differentiation.
abstract: Stem cells in adult tissues are constantly exposed to genotoxic stress and also accumulate DNA damage with age. However, it remains largely unknown how DNA damage affects both stem cell self-renewal and differentiation. In this study, we show that DNA damage retards germline stem cell (GSC) self-renewal and progeny differentiation in a Lok kinase-dependent manner in the Drosophila ovary. Both heatshock-inducible endonuclease I-CreI expression and X-ray irradiation can efficiently introduce double-strand breaks in GSCs and their progeny, resulting in a rapid GSC loss and a GSC progeny differentiation defect. Surprisingly, the elimination of Lok or its kinase activity can almost fully rescue the GSC loss and the progeny differentiation defect caused by DNA damage induced by I-CreI or X-ray. In addition, the reduction in bone morphogenetic protein signaling and Shotgun expression only makes a limited contribution to DNA damage-induced GSC loss. Finally, DNA damage also decreases the expression of the master differentiation factor Bam in a Lok-dependent manner, which helps explain the GSC progeny differentiation defect. Therefore, this study demonstrates, for the first time in vivo, that Lok kinase activation is required for the DNA damage-mediated disruption of adult stem cell self-renewal and lineage differentiation, and might also offer novel insight into how DNA damage causes tissue aging and cancer formation.
authors.affiliation: Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA.|Department of Cell Biology and Anatomy, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Xing
authors.identifier: 0000-0001-6914-0173
authors.initials: X
authors.lastname: Ma
authors.affiliation: Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA.
authors.forename: Yingying
authors.identifier: 0000-0002-4908-0828
authors.initials: Y
authors.lastname: Han
authors.affiliation: Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Song
authors.affiliation: Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA.
authors.forename: Trieu
authors.initials: T
authors.lastname: Do
authors.affiliation: Tsinghua University School of Medicine, Beijing 100084, China.
authors.forename: Zhihao
authors.identifier: 0000-0001-6736-8924
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Tsinghua University School of Medicine, Beijing 100084, China.
authors.forename: Jianquan
authors.initials: J
authors.lastname: Ni
authors.affiliation: Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA tgx@stowers.org.|Department of Cell Biology and Anatomy, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Ting
authors.identifier: 0000-0003-4784-2048
authors.initials: T
authors.lastname: Xie
mesh_terms: D000375:Aging / Q000235:genetics / Q000502:physiology; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D019070:Cell Lineage / Q000235:genetics; D000066673:Cell Self Renewal / Q000502:physiology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D064447:Checkpoint Kinase 2 / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000235:genetics*; D004262:DNA Restriction Enzymes / Q000378:metabolism; D003850:Deoxyribonuclease I / Q000378:metabolism; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D005854:Germ Cells / Q000166:cytology*; D013234:Stem Cells / Q000166:cytology*
chemical_list: D029721:Drosophila Proteins; C091674:bam protein, Drosophila; D064447:Checkpoint Kinase 2; C112435:lok protein, Drosophila; D004262:DNA Restriction Enzymes; C048901:endodeoxyribonuclease CreI; D003850:Deoxyribonuclease I
keywords: CHK2; Differentiation; Germline stem cell; Lok; Niche; Self-renewal