Homocysteine aggravates DNA damage by impairing the FA/Brca1 Pathway in NE4C murine neural stem cells

Yan, Yana; Yin, Yandan; Feng, Xiaofang; Chen, Yuan; Shi, Jiamin; Weng, Huachun; Wang, Dan

doi:10.7150/ijms.49246



Theranostics

International Journal of Biological Sciences

Nanotheranostics

Journal of Cancer

Journal of Genomics

Global reach, higher impact

Full Text | PDF

Int J Med Sci 2020; 17(16):2477-2486. doi:10.7150/ijms.49246 This issue Cite

Research Paper

Homocysteine aggravates DNA damage by impairing the FA/Brca1 Pathway in NE4C murine neural stem cells

Yana Yan^1*, Yandan Yin^2*, Xiaofang Feng^1*, Yuan Chen¹, Jiamin Shi¹, Huachun Weng^1✉, Dan Wang^1✉

1. Department of Pediatrics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, P. R. China.
2. Department of Pediatrics, Taizhou Women and Children's Hospital of Wenzhou Medical University, Taizhou 318000, Zhejiang, P. R. China.
*These authors contributed equally to this work.

Citation:

Yan Y, Yin Y, Feng X, Chen Y, Shi J, Weng H, Wang D. Homocysteine aggravates DNA damage by impairing the FA/Brca1 Pathway in NE4C murine neural stem cells. Int J Med Sci 2020; 17(16):2477-2486. doi:10.7150/ijms.49246. https://www.medsci.org/v17p2477.htm

Other styles

Abstract

There is existing evidence that elevated homocysteine (Hcy) levels are risk factors for some neurodegenerative disorders. The pathogenesis of neurological diseases could be contributed to excessive cell dysfunction and death caused by defective DNA damage response (DDR) and accumulated DNA damage. Hcy is a neurotoxic amino acid and acts as a DNA damage inducer. However, it is not clear whether Hcy participates in the DDR. To investigate the effects of Hcy on DNA damage and the DDR, we employed mitomycin C (MMC) to cause DNA damage in NE4C murine neural stem cells (NSCs). Compared to treatment with MMC alone, we found that co-treatment with MMC and Hcy worsened DNA damage and increased death in NE4C cells. Intriguingly, in this DNA damage model mimicked by MMC, immunoblotting results showed that the monoubiquitination levels of Fanconi anemia complementation group I (Fanci) and Fanconi anemia complementation group D2 (Fancd2) were decreased to about 60.3% and 55.7% by supplementing cell culture medium with Hcy, indicating Hcy inactivates the function of Fanci and Fancd2 in DNA damage conditions. Given Breast Cancer 1 (BRCA1) is an important downstream of FANCD2, we next detected the interaction between Fancd2 and Brca1 in NE4C cells. Compared to treatment with MMC alone, the Fancd2-Brca1 interaction and the amount of Brca1 on chromatin were decreased when cells were co-exposed to MMC and Hcy, suggesting Hcy could impair the Fanconi anemia (FA)/Brca1 pathway. Taken together, our study demonstrates that Hcy may enhance cell death, which contributes to the accumulation of DNA damage and promotion of hypersensitivity to cytotoxicity by impairing the FA/Brca1 pathway in murine NSCs in the presence of DNA damage.

Keywords: homocysteine, DNA damage, Fanconi anemia pathway, Brca1, neural stem cell

Citation styles

APA

Yan, Y., Yin, Y., Feng, X., Chen, Y., Shi, J., Weng, H., Wang, D. (2020). Homocysteine aggravates DNA damage by impairing the FA/Brca1 Pathway in NE4C murine neural stem cells. International Journal of Medical Sciences, 17(16), 2477-2486. https://doi.org/10.7150/ijms.49246.

ACS

Yan, Y.; Yin, Y.; Feng, X.; Chen, Y.; Shi, J.; Weng, H.; Wang, D. Homocysteine aggravates DNA damage by impairing the FA/Brca1 Pathway in NE4C murine neural stem cells. Int. J. Med. Sci. 2020, 17 (16), 2477-2486. DOI: 10.7150/ijms.49246.

NLM

CSE

Yan Y, Yin Y, Feng X, Chen Y, Shi J, Weng H, Wang D. 2020. Homocysteine aggravates DNA damage by impairing the FA/Brca1 Pathway in NE4C murine neural stem cells. Int J Med Sci. 17(16):2477-2486.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.