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hnRNP G/RBMX enhances HPV16 E2 mRNA splicing through a novel splicing enhancer and inhibits production of spliced E7 oncogene mRNAs

Hao, Chengyu LU ; Zheng, Yunji LU ; Jönsson, Johanna LU orcid ; Cui, Xiaoxu LU ; Yu, Haoran LU ; Wu, Chengjun ; Kajitani, Naoko LU and Schwartz, Stefan LU (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
; ; ; ; ; ; and
organization
publishing date
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}},
}