hnRNP G/RBMX enhances HPV16 E2 mRNA splicing through a novel splicing enhancer and inhibits production of spliced E7 oncogene mRNAs
(2022) In Nucleic Acids Research 50(7). p.3867-3891- Abstract
Human papillomavirus type 16 (HPV16) E2 is an essential HPV16 protein. We have investigated how HPV16 E2 expression is regulated and have identifed a splicing enhancer that is required for production of HPV16 E2 mRNAs. This uridine-less splicing enhancer sequence (ACGAGGACGAGGACAAGGA) contains 84% adenosine and guanosine and 16% cytosine and consists of three 'AC(A/G)AGG'-repeats. Mutational inactivation of the splicing enhancer reduced splicing to E2-mRNA specific splice site SA2709 and resulted in increased levels of unspliced E1-encoding mRNAs. The splicing enhancer sequence interacted with cellular RNA binding protein hnRNP G that promoted splicing to SA2709 and enhanced E2 mRNA production. The splicing-enhancing function of hnRNP G... (More)
Human papillomavirus type 16 (HPV16) E2 is an essential HPV16 protein. We have investigated how HPV16 E2 expression is regulated and have identifed a splicing enhancer that is required for production of HPV16 E2 mRNAs. This uridine-less splicing enhancer sequence (ACGAGGACGAGGACAAGGA) contains 84% adenosine and guanosine and 16% cytosine and consists of three 'AC(A/G)AGG'-repeats. Mutational inactivation of the splicing enhancer reduced splicing to E2-mRNA specific splice site SA2709 and resulted in increased levels of unspliced E1-encoding mRNAs. The splicing enhancer sequence interacted with cellular RNA binding protein hnRNP G that promoted splicing to SA2709 and enhanced E2 mRNA production. The splicing-enhancing function of hnRNP G mapped to amino acids 236-286 of hnRNP G that were also shown to interact with splicing factor U2AF65. The interactions between hnRNP G and HPV16 E2 mRNAs and U2AF65 increased in response to keratinocyte differentiation as well as by the induction of the DNA damage response (DDR). The DDR reduced sumoylation of hnRNP G and pharmacological inhibition of sumoylation enhanced HPV16 E2 mRNA splicing and interactions between hnRNP G and E2 mRNAs and U2AF65. Intriguingly, hnRNP G also promoted intron retention of the HPV16 E6 coding region thereby inhibiting production of spliced E7 oncogene mRNAs.
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- author
- Hao, Chengyu LU ; Zheng, Yunji LU ; Jönsson, Johanna LU ; Cui, Xiaoxu LU ; Yu, Haoran LU ; Wu, Chengjun ; Kajitani, Naoko LU and Schwartz, Stefan LU
- organization
- publishing date
- 2022-04-22
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- DNA-Binding Proteins/genetics, Heterogeneous-Nuclear Ribonucleoproteins/metabolism, Human papillomavirus 16/genetics, Humans, Oncogene Proteins, Viral/genetics, Oncogenes, Papillomavirus E7 Proteins/genetics, RNA Splicing, RNA, Messenger/genetics
- in
- Nucleic Acids Research
- volume
- 50
- issue
- 7
- pages
- 3867 - 3891
- publisher
- Oxford University Press
- external identifiers
-
- scopus:85128608513
- pmid:35357488
- ISSN
- 1362-4962
- DOI
- 10.1093/nar/gkac213
- language
- English
- LU publication?
- yes
- additional info
- © The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.
- id
- fd05a1d2-8db5-4415-9db0-0518523ba1a5
- date added to LUP
- 2022-06-29 13:47:49
- date last changed
- 2024-03-21 08:33:21
@article{fd05a1d2-8db5-4415-9db0-0518523ba1a5, abstract = {{<p>Human papillomavirus type 16 (HPV16) E2 is an essential HPV16 protein. We have investigated how HPV16 E2 expression is regulated and have identifed a splicing enhancer that is required for production of HPV16 E2 mRNAs. This uridine-less splicing enhancer sequence (ACGAGGACGAGGACAAGGA) contains 84% adenosine and guanosine and 16% cytosine and consists of three 'AC(A/G)AGG'-repeats. Mutational inactivation of the splicing enhancer reduced splicing to E2-mRNA specific splice site SA2709 and resulted in increased levels of unspliced E1-encoding mRNAs. The splicing enhancer sequence interacted with cellular RNA binding protein hnRNP G that promoted splicing to SA2709 and enhanced E2 mRNA production. The splicing-enhancing function of hnRNP G mapped to amino acids 236-286 of hnRNP G that were also shown to interact with splicing factor U2AF65. The interactions between hnRNP G and HPV16 E2 mRNAs and U2AF65 increased in response to keratinocyte differentiation as well as by the induction of the DNA damage response (DDR). The DDR reduced sumoylation of hnRNP G and pharmacological inhibition of sumoylation enhanced HPV16 E2 mRNA splicing and interactions between hnRNP G and E2 mRNAs and U2AF65. Intriguingly, hnRNP G also promoted intron retention of the HPV16 E6 coding region thereby inhibiting production of spliced E7 oncogene mRNAs.</p>}}, author = {{Hao, Chengyu and Zheng, Yunji and Jönsson, Johanna and Cui, Xiaoxu and Yu, Haoran and Wu, Chengjun and Kajitani, Naoko and Schwartz, Stefan}}, issn = {{1362-4962}}, keywords = {{DNA-Binding Proteins/genetics; Heterogeneous-Nuclear Ribonucleoproteins/metabolism; Human papillomavirus 16/genetics; Humans; Oncogene Proteins, Viral/genetics; Oncogenes; Papillomavirus E7 Proteins/genetics; RNA Splicing; RNA, Messenger/genetics}}, language = {{eng}}, month = {{04}}, number = {{7}}, pages = {{3867--3891}}, publisher = {{Oxford University Press}}, series = {{Nucleic Acids Research}}, title = {{hnRNP G/RBMX enhances HPV16 E2 mRNA splicing through a novel splicing enhancer and inhibits production of spliced E7 oncogene mRNAs}}, url = {{http://dx.doi.org/10.1093/nar/gkac213}}, doi = {{10.1093/nar/gkac213}}, volume = {{50}}, year = {{2022}}, }