Fanconi anemia protein FANCD2 is activated by AICAR, a modulator of AMPK and cellular energy metabolism.
FANCD2 is a pivotal molecule in the pathogenesis of Fanconi anemia (FA), an autosomal recessive human syndrome with diverse clinical phenotypes, including cancer predisposition, short stature, and hematological abnormalities. In our previous study, we detected the functional association of FANC proteins, whose mutations are responsible for the onset of FA, with AMPK in response to DNA interstrand crosslinking lesions. Because AMPK is well known as a critical sensing molecule for cellular energy levels, we checked whether FANCD2 activation occurs after treatments affecting AMPK and/or cellular energy status. Among the treatments tested, AMPK-activating 5-aminoimidazole-4-carboxamide-ribonucleoside (AICAR) induced monoubiquitination and nuclear foci formation of FANCD2, which are biomarkers of FANCD2 activation. FANCD2 activation was abolished by treatments with Compound C, an AMPK inhibitor, or after AMPKα1 knockdown, substantiating the involvement of AMPK in AICAR-induced FANCD2 activation. Similarly, FANCA protein, which is a component of the FA core complex monoubiquitinating FANCD2, was required for this event. Furthermore, FANCD2 repression enhanced cell death upon AICAR treatments in transformed fibroblasts and cell cycle arrest in the renal cell carcinoma cell line Caki-1. Overall, this study showed FANCD2 involvement in response to AICAR, a chemical modulating cellular energy metabolism.
Cancer Cell and Molecular Biology Branch Research Institute National Cancer Center Goyang Korea.
Min Jeong
MJ
Chun
Cancer Cell and Molecular Biology Branch Research Institute National Cancer Center Goyang Korea.
Hana
H
Choi
Precision Medicine Branch Research Institute National Cancer Center Goyang Korea.
Dong Wha
DW
Jun
Precision Medicine Branch Research Institute National Cancer Center Goyang Korea.
Sunshin
S
Kim
Comparative Biomedicine Research Branch Research Institute National Cancer Center Goyang Korea.
Yong-Nyun
YN
Kim
Cancer Cell and Molecular Biology Branch Research Institute National Cancer Center Goyang Korea.
Soo-Youl
SY
Kim
Cancer Cell and Molecular Biology Branch Research Institute National Cancer Center Goyang Korea.
Chang-Hun
0000-0002-4083-2077
CH
Lee
AICAR; AMP‐activated protein kinase; FANCD2