Genotoxic stress abrogates renewal of melanocyte stem cells by triggering their differentiation.
Somatic stem cell depletion due to the accumulation of DNA damage has been implicated in the appearance of aging-related phenotypes. Hair graying, a typical sign of aging in mammals, is caused by the incomplete maintenance of melanocyte stem cells (MSCs) with age. Here, we report that irreparable DNA damage, as caused by ionizing radiation, abrogates renewal of MSCs in mice. Surprisingly, the DNA-damage response triggers MSC differentiation into mature melanocytes in the niche, rather than inducing their apoptosis or senescence. The resulting MSC depletion leads to irreversible hair graying. Furthermore, deficiency of Ataxia-telangiectasia mutated (ATM), a central transducer kinase of the DNA-damage response, sensitizes MSCs to ectopic differentiation, demonstrating that the kinase protects MSCs from their premature differentiation by functioning as a "stemness checkpoint" to maintain the stem cell quality and quantity.
Inomata
Ken
K
Division of Stem Cell Medicine, Center for Cancer and Stem Cell Research, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan.
Aoto
Takahiro
T
Binh
Nguyen Thanh
NT
Okamoto
Natsuko
N
Tanimura
Shintaro
S
Wakayama
Tomohiko
T
Iseki
Shoichi
S
Hara
Eiji
E
Masunaga
Takuji
T
Shimizu
Hiroshi
H
Nishimura
Emi K
EK
D000375:Aging; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism; D006197:Hair / Q000166:cytology / Q000473:pathology / Q000503:physiopathology; D008544:Melanocytes / Q000166:cytology* / Q000528:radiation effects*; D020460:Melanosomes / Q000378:metabolism; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology* / Q000528:radiation effects*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D014965:X-Rays
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases