Open AccessFanconi anemia protein FANCD 2 is activated by AICAR , a modulator of AMPK and cellular energy metabolism
Author(s) -
Chun Min Jeong,
Choi Hana,
Jun Dong Wha,
Kim Sunshin,
Kim YongNyun,
Kim SooYoul,
Lee ChangHun
Publication year - 2017
Publication title -
febs open bio
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.718
H-Index - 31
ISSN - 2211-5463
DOI - 10.1002/2211-5463.12185
Subject(s) - fancd2 , ampk , fanconi anemia , gene knockdown , microbiology and biotechnology , chemistry , biology , cancer research , protein kinase a , cell culture , dna repair , biochemistry , phosphorylation , genetics , dna
FANCD 2 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 FANCD 2 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 FANCD 2, which are biomarkers of FANCD 2 activation. FANCD 2 activation was abolished by treatments with Compound C, an AMPK inhibitor, or after AMPK α1 knockdown, substantiating the involvement of AMPK in AICAR ‐induced FANCD 2 activation. Similarly, FANCA protein, which is a component of the FA core complex monoubiquitinating FANCD 2, was required for this event. Furthermore, FANCD 2 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 FANCD 2 involvement in response to AICAR , a chemical modulating cellular energy metabolism.