TY - JOUR
T1 - Disabling the fanconi anemia pathway in stem cells leads to radioresistance and genomic instability
AU - Deng, Xinzhu
AU - Tchieu, Jason
AU - Higginson, Daniel S.
AU - Hsu, Kuo Shun
AU - Feldman, Regina
AU - Studer, Lorenz
AU - Shaham, Shai
AU - Powell, Simon N.
AU - Fuks, Zvi
AU - Kolesnick, Richard
N1 - Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/7/1
Y1 - 2021/7/1
N2 - Fanconi anemia is an inherited genome instability syndrome characterized by interstrand cross-link hypersensitivity, congenital defects, bone marrow failure, and cancer predisposition. Although DNArepair mediated by Fanconi anemia genes has been extensively studied, how inactivation of these genes leads to specific cellular phenotypic consequences associated with Fanconi anemia is not well understood. Here we report that Fanconi anemia stem cells in the C. elegans germline and in murine embryos display marked nonhomologous end joining (NHEJ)-dependent radiation resistance, leading to survival of progeny cells carrying genetic lesions. In contrast, DNA cross-linking does not induce generational genomic instability in Fanconi anemia stem cells, as widely accepted, but rather drives NHEJ-dependent apoptosis in both species. These findings suggest that Fanconi anemia is a stem cell disease reflecting inappropriate NHEJ, which is mutagenic and carcinogenic as a result of DNA misrepair, while marrow failure represents hematopoietic stem cell apoptosis.
AB - Fanconi anemia is an inherited genome instability syndrome characterized by interstrand cross-link hypersensitivity, congenital defects, bone marrow failure, and cancer predisposition. Although DNArepair mediated by Fanconi anemia genes has been extensively studied, how inactivation of these genes leads to specific cellular phenotypic consequences associated with Fanconi anemia is not well understood. Here we report that Fanconi anemia stem cells in the C. elegans germline and in murine embryos display marked nonhomologous end joining (NHEJ)-dependent radiation resistance, leading to survival of progeny cells carrying genetic lesions. In contrast, DNA cross-linking does not induce generational genomic instability in Fanconi anemia stem cells, as widely accepted, but rather drives NHEJ-dependent apoptosis in both species. These findings suggest that Fanconi anemia is a stem cell disease reflecting inappropriate NHEJ, which is mutagenic and carcinogenic as a result of DNA misrepair, while marrow failure represents hematopoietic stem cell apoptosis.
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U2 - 10.1158/0008-5472.CAN-20-3309
DO - 10.1158/0008-5472.CAN-20-3309
M3 - Article
C2 - 33941615
AN - SCOPUS:85109017373
SN - 0008-5472
VL - 81
SP - 3706
EP - 3716
JO - Cancer Research
JF - Cancer Research
IS - 13
ER -