Cancer letters, 2019-05, Vol.449, p.114-124
2019
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- Autor(en) / Beteiligte
- Titel
- USP39 regulates DNA damage response and chemo-radiation resistance by deubiquitinating and stabilizing CHK2
- Ist Teil von
- Cancer letters, 2019-05, Vol.449, p.114-124
- Ort / Verlag
- Ireland: Elsevier B.V
- Erscheinungsjahr
- 2019
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- The serine/threonine kinase, CHK2 (checkpoint kinase 2), is a key mediator in DNA damage response and a tumor suppressor, which is implicated in promoting cell cycle arrest, apoptosis and DNA repair. Accumulating evidence suggests that these functions are primarily exerted through phosphorylation downstream factors such as p53 and BRCA1. Recent studies have shown that ubiquitination is an important mode of regulation of CHK2. However, it remains largely unclear whether deubiquitinases participate in regulation of CHK2. Here, we report that a deubiquitinase, USP39, is a new regulator of CHK2. Mechanistically, USP39 deubiquitinates and stabilizes CHK2, which in turn enhances CHK2 stability. Short hairpin RNA (shRNA) mediated knockdown of USP39 led to deregulate CHK2, which resulted in compromising the DNA damage-induced G2/M checkpoint, decreasing apoptosis, and conferring cancer cells resistance to chemotherapy drugs and radiation treatment. Collectively, we identify USP39 as a novel regulator of CHK2 in the DNA damage response. •USP39 deubiquitinates and stabilizes CHK2 both in vitro and in vivo.•USP39 regulates apoptosis and G2/M cell cycle checkpoint through CHK2 in response to DNA damage.•The expression of USP39 and CHK2 are highly correlative in lung cancer tissue.•USP39 regulates chemo-radiation resistance through CHK2 in lung cancer cells.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0304-3835eISSN: 1872-7980DOI: 10.1016/j.canlet.2019.02.015Titel-ID: cdi_proquest_miscellaneous_2185873088
- Format
- –
- Schlagworte
- A549 Cells, Apoptosis, BRCA1 protein, Breast cancer, Cancer, Cancer therapies, Cell Cycle, Cell Line, Tumor, Checkpoint Kinase 2 - chemistry, Checkpoint Kinase 2 - metabolism, Chemo-radiation resistance, Chemotherapy, CHK2, CHK2 protein, Conflicts of interest, Deoxyribonucleic acid, Deubiquitination, DNA, DNA Damage, DNA Repair, Drug resistance, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, Humans, Immunoglobulins, Kinases, Lung cancer, Lung Neoplasms - genetics, Lung Neoplasms - metabolism, p53 Protein, Phosphorylation, Plasmids, Prostate, Protein Stability, Protein-serine/threonine kinase, Proteins, Radiation, Radiation therapy, Radiation Tolerance, Ribonucleic acid, RNA, Tumor suppressor genes, Ubiquitin-Specific Proteases - metabolism, Ubiquitination, Up-Regulation, USP39