DNA damage-induced activation of ATM promotes β-TRCP-mediated ARID1A ubiquitination and destruction in gastric cancer cells
Abstract Background AT-rich interactive domain-containing protein 1A (ARID1A) is a subunit of the mammary SWI/SNF chromatin remodeling complex and a tumor suppressor protein. The loss of ARID1A been observed in several types of human cancers and associated with poor patient prognosis. Previously, we...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2019-06-01
|
| Series: | Cancer Cell International |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12935-019-0878-y |
| _version_ | 1818239995783151616 |
|---|---|
| author | Zhou-hua Jiang Tao Peng Hai-long Qian Cai-de Lu Feng Qiu Su-zhan Zhang |
| author_facet | Zhou-hua Jiang Tao Peng Hai-long Qian Cai-de Lu Feng Qiu Su-zhan Zhang |
| author_sort | Zhou-hua Jiang |
| collection | DOAJ |
| description | Abstract Background AT-rich interactive domain-containing protein 1A (ARID1A) is a subunit of the mammary SWI/SNF chromatin remodeling complex and a tumor suppressor protein. The loss of ARID1A been observed in several types of human cancers and associated with poor patient prognosis. Previously, we have reported that ARID1A protein was rapidly ubiquitinated and destructed in gastric cancer cells during DNA damage response. However, the ubiquitin e3 ligase that mediated this process remains unclear. Materials and methods The interaction between ARID1A and β-TRCP was verified by co-immunoprecipitation (Co-IP) assay. The degron site of ARID1A protein was analyzed by bioinformatics assay. Short hairpin RNAs (shRNAs) were used to knockdown (KD) gene expression. Results Here we show that DNA damage promotes ARID1A ubiquitination and subsequent destruction via the ubiquitin E3 ligase complex SCFβ-TRCP. β-TRCP recognizes ARID1A through a canonical degron site (DSGXXS) after its phosphorylation in response to DNA damage. Notably, genetic inactivation of the Ataxia Telangiectasia Mutated (ATM) kinase impaired DNA damage-induced ARID1A destruction. Conclusions Our studies provide a novel molecular mechanism for the negative regulation of ARID1A by β-TRCP and ATM in DNA damaged gastric cancer cells. |
| first_indexed | 2024-12-12T13:06:25Z |
| format | Article |
| id | doaj.art-60036a0d1b224fb6ace43df27b332a59 |
| institution | Directory Open Access Journal |
| issn | 1475-2867 |
| language | English |
| last_indexed | 2024-12-12T13:06:25Z |
| publishDate | 2019-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer Cell International |
| spelling | doaj.art-60036a0d1b224fb6ace43df27b332a592022-12-22T00:23:38ZengBMCCancer Cell International1475-28672019-06-011911710.1186/s12935-019-0878-yDNA damage-induced activation of ATM promotes β-TRCP-mediated ARID1A ubiquitination and destruction in gastric cancer cellsZhou-hua Jiang0Tao Peng1Hai-long Qian2Cai-de Lu3Feng Qiu4Su-zhan Zhang5Zhejiang University School of MedicineDepartment of Gastrointestinal Surgery, Ningbo Medical Center, Li Huili Eastern HospitalDepartment of Gastrointestinal Surgery, Ningbo Medical Center, Li Huili Eastern HospitalDepartment of Gastrointestinal Surgery, Ningbo Medical Center, Li Huili Eastern HospitalDepartment of Gastrointestinal Surgery, Ningbo Medical Center, Li Huili Eastern HospitalDepartment of Surgical Oncology, The Second Affiliated Hospital, Zhejiang University School of MedicineAbstract Background AT-rich interactive domain-containing protein 1A (ARID1A) is a subunit of the mammary SWI/SNF chromatin remodeling complex and a tumor suppressor protein. The loss of ARID1A been observed in several types of human cancers and associated with poor patient prognosis. Previously, we have reported that ARID1A protein was rapidly ubiquitinated and destructed in gastric cancer cells during DNA damage response. However, the ubiquitin e3 ligase that mediated this process remains unclear. Materials and methods The interaction between ARID1A and β-TRCP was verified by co-immunoprecipitation (Co-IP) assay. The degron site of ARID1A protein was analyzed by bioinformatics assay. Short hairpin RNAs (shRNAs) were used to knockdown (KD) gene expression. Results Here we show that DNA damage promotes ARID1A ubiquitination and subsequent destruction via the ubiquitin E3 ligase complex SCFβ-TRCP. β-TRCP recognizes ARID1A through a canonical degron site (DSGXXS) after its phosphorylation in response to DNA damage. Notably, genetic inactivation of the Ataxia Telangiectasia Mutated (ATM) kinase impaired DNA damage-induced ARID1A destruction. Conclusions Our studies provide a novel molecular mechanism for the negative regulation of ARID1A by β-TRCP and ATM in DNA damaged gastric cancer cells.http://link.springer.com/article/10.1186/s12935-019-0878-yARID1Aβ-TRCPPhosphodegronDNA damage |
| spellingShingle | Zhou-hua Jiang Tao Peng Hai-long Qian Cai-de Lu Feng Qiu Su-zhan Zhang DNA damage-induced activation of ATM promotes β-TRCP-mediated ARID1A ubiquitination and destruction in gastric cancer cells Cancer Cell International ARID1A β-TRCP Phosphodegron DNA damage |
| title | DNA damage-induced activation of ATM promotes β-TRCP-mediated ARID1A ubiquitination and destruction in gastric cancer cells |
| title_full | DNA damage-induced activation of ATM promotes β-TRCP-mediated ARID1A ubiquitination and destruction in gastric cancer cells |
| title_fullStr | DNA damage-induced activation of ATM promotes β-TRCP-mediated ARID1A ubiquitination and destruction in gastric cancer cells |
| title_full_unstemmed | DNA damage-induced activation of ATM promotes β-TRCP-mediated ARID1A ubiquitination and destruction in gastric cancer cells |
| title_short | DNA damage-induced activation of ATM promotes β-TRCP-mediated ARID1A ubiquitination and destruction in gastric cancer cells |
| title_sort | dna damage induced activation of atm promotes β trcp mediated arid1a ubiquitination and destruction in gastric cancer cells |
| topic | ARID1A β-TRCP Phosphodegron DNA damage |
| url | http://link.springer.com/article/10.1186/s12935-019-0878-y |
| work_keys_str_mv | AT zhouhuajiang dnadamageinducedactivationofatmpromotesbtrcpmediatedarid1aubiquitinationanddestructioningastriccancercells AT taopeng dnadamageinducedactivationofatmpromotesbtrcpmediatedarid1aubiquitinationanddestructioningastriccancercells AT hailongqian dnadamageinducedactivationofatmpromotesbtrcpmediatedarid1aubiquitinationanddestructioningastriccancercells AT caidelu dnadamageinducedactivationofatmpromotesbtrcpmediatedarid1aubiquitinationanddestructioningastriccancercells AT fengqiu dnadamageinducedactivationofatmpromotesbtrcpmediatedarid1aubiquitinationanddestructioningastriccancercells AT suzhanzhang dnadamageinducedactivationofatmpromotesbtrcpmediatedarid1aubiquitinationanddestructioningastriccancercells |