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Promyelocytic leukemia proteins regulate fanconi anemia gene expression

Authors
Munkhjargal, A.Kim, M.-J.Kim, D.-Y.Jeon, Y.-J.Kee, Y.-H.Kim, L.-K.Kim, Y.-H.
Issue Date
Aug-2021
Publisher
MDPI AG
Keywords
CHK1 inhibitors; Fanconi anemia; Interstrand DNA crosslink; PML nuclear body
Citation
International Journal of Molecular Sciences, v.22, no.15, pp.1 - 14
Journal Title
International Journal of Molecular Sciences
Volume
22
Number
15
Start Page
1
End Page
14
URI
https://scholarworks.sookmyung.ac.kr/handle/2020.sw.sookmyung/146493
DOI
10.3390/ijms22157782
ISSN
1661-6596
Abstract
Promyelocytic leukemia (PML) protein is the core component of subnuclear structures called PML nuclear bodies that are known to play important roles in cell survival, DNA damage responses, and DNA repair. Fanconi anemia (FA) proteins are required for repairing interstrand DNA crosslinks (ICLs). Here we report a novel role of PML proteins, regulating the ICL repair pathway. We found that depletion of the PML protein led to the significant reduction of damage-induced FANCD2 mono-ubiquitination and FANCD2 foci formation. Consistently, the cells treated with siRNA against PML showed enhanced sensitivity to a crosslinking agent, mitomycin C. Further studies showed that depletion of PML reduced the protein expression of FANCA, FANCG, and FANCD2 via reduced transcriptional activity. Interestingly, we observed that damage-induced CHK1 phosphorylation was severely impaired in cells with depleted PML, and we demonstrated that CHK1 regulates FANCA, FANCG, and FANCD2 transcription. Finally, we showed that inhibition of CHK1 phosphorylation further sensitized cancer cells to mitomycin C. Taken together, these findings suggest that the PML is critical for damage-induced CHK1 phosphorylation, which is important for FA gene expression and for repairing ICLs. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
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