PMID- 34615711 OWN - NLM STAT- MEDLINE DCOM- 20211214 LR - 20220408 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 118 IP - 41 DP - 2021 Oct 12 TI - High-risk human papillomavirus-18 uses an mRNA sequence to synthesize oncoprotein E6 in tumors. LID - 10.1073/pnas.2108359118 [doi] LID - e2108359118 AB - Cervical cancer is the fourth most common cause of cancer in women worldwide in terms of both incidence and mortality. Persistent infection with high-risk types of human papillomavirus (HPV), namely 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68, constitute a necessary cause for the development of cervical cancer. Viral oncoproteins E6 and E7 play central roles in the carcinogenic process by virtue of their interactions with cell master proteins such as p53, retinoblastoma (Rb), mammalian target of rapamycin (mTOR), and c-MYC. For the synthesis of E6 and E7, HPVs use a bicistronic messenger RNA (mRNA) that has been studied in cultured cells. Here, we report that in cervical tumors, HPV-18, -39, and -45 transcribe E6/E7 mRNAs with extremely short 5' untranslated regions (UTRs) or even lacking a 5' UTR (i.e., zero to three nucleotides long) to express E6. We show that the translation of HPV-18 E6 cistron is regulated by the motif ACCaugGCGCG(C/A)UUU surrounding the AUG start codon, which we term Translation Initiation of Leaderless mRNAs (TILM). This motif is conserved in all HPV types of the phylogenetically coherent group forming genus alpha, species 7, which infect mucosal epithelia. We further show that the translation of HPV-18 E6 largely relies on the cap structure and eIF4E and eIF4AI, two key translation initiation factors linking translation and cancer but does not involve scanning. Our results support the notion that E6 forms the center of the positive oncogenic feedback loop node involving eIF4E, the mTOR cascade, and p53. FAU - Garcia, Alejandra AU - Garcia A AUID- ORCID: 0000-0002-3040-612X AD - Unit of Biomedical Research on Cancer, Laboratory of Translation and Cancer, National Institute of Cancer (Instituto Nacional de Cancerologia), Mexico City 14080, Mexico. FAU - Maldonado, Giovanna AU - Maldonado G AUID- ORCID: 0000-0001-9247-8746 AD - Unit of Biomedical Research on Cancer, Laboratory of Translation and Cancer, National Institute of Cancer (Instituto Nacional de Cancerologia), Mexico City 14080, Mexico. FAU - Gonzalez, Jose L AU - Gonzalez JL AUID- ORCID: 0000-0002-1807-9410 AD - Unit of Biomedical Research on Cancer, Laboratory of Virus and Cancer, National Institute of Cancer (Instituto Nacional de Cancerologia), Mexico City 14080, Mexico. FAU - Svitkin, Yuri AU - Svitkin Y AUID- ORCID: 0000-0003-3819-2143 AD - Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal H3A 1A3, QC, Canada. FAU - Cantu, David AU - Cantu D AD - Unit of Biomedical Research on Cancer, Division of Basic Research, National Institute of Cancer, Mexico City 14080, Mexico. FAU - Garcia-Carranca, Alejandro AU - Garcia-Carranca A AUID- ORCID: 0000-0003-1220-5014 AD - Unit of Biomedical Research on Cancer, Laboratory of Virus and Cancer, National Institute of Cancer (Instituto Nacional de Cancerologia), Mexico City 14080, Mexico. AD - Institute of Biomedical Research, Universidad Nacional Autonoma de Mexico, Mexico City 04510, Mexico. FAU - Sonenberg, Nahum AU - Sonenberg N AUID- ORCID: 0000-0002-4707-8759 AD - Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal H3A 1A3, QC, Canada. FAU - Hernandez, Greco AU - Hernandez G AUID- ORCID: 0000-0002-5318-4443 AD - Unit of Biomedical Research on Cancer, Laboratory of Translation and Cancer, National Institute of Cancer (Instituto Nacional de Cancerologia), Mexico City 14080, Mexico; ghernandezr@incan.edu.mx. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (5' Untranslated Regions) RN - 0 (Codon, Initiator) RN - 0 (DNA-Binding Proteins) RN - 0 (E6 protein, Human papillomavirus type 18) RN - 0 (E7 protein, Human papillomavirus type 18) RN - 0 (EIF4A1 protein, human) RN - 0 (EIF4E protein, human) RN - 0 (Eukaryotic Initiation Factor-4E) RN - 0 (Oncogene Proteins, Viral) RN - 0 (RNA, Messenger) RN - 0 (RNA, Viral) RN - 0 (TP53 protein, human) RN - 0 (Tumor Suppressor Protein p53) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.7.- (Eukaryotic Initiation Factor-4A) SB - IM MH - 5' Untranslated Regions/genetics MH - Cell Line, Tumor MH - Codon, Initiator/genetics MH - DNA-Binding Proteins/biosynthesis/*genetics MH - Eukaryotic Initiation Factor-4A/*genetics MH - Eukaryotic Initiation Factor-4E/*genetics MH - Female MH - Gene Expression Regulation, Viral/genetics MH - HEK293 Cells MH - HaCaT Cells MH - HeLa Cells MH - Human papillomavirus 18/*genetics/metabolism MH - Humans MH - Oncogene Proteins, Viral/biosynthesis/*genetics MH - Peptide Chain Initiation, Translational/genetics MH - RNA, Messenger/*genetics MH - RNA, Viral/genetics MH - TOR Serine-Threonine Kinases/genetics MH - Tumor Suppressor Protein p53/genetics MH - Uterine Cervical Neoplasms/drug therapy/pathology/virology PMC - PMC8522272 OTO - NOTNLM OT - E6 OT - HPV OT - TILM OT - cancer OT - translation COIS- The authors declare no competing interest. EDAT- 2021/10/08 06:00 MHDA- 2021/12/15 06:00 PMCR- 2022/04/06 CRDT- 2021/10/07 06:00 PHST- 2021/08/17 00:00 [accepted] PHST- 2021/10/07 06:00 [entrez] PHST- 2021/10/08 06:00 [pubmed] PHST- 2021/12/15 06:00 [medline] PHST- 2022/04/06 00:00 [pmc-release] AID - 2108359118 [pii] AID - 202108359 [pii] AID - 10.1073/pnas.2108359118 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2021 Oct 12;118(41):e2108359118. doi: 10.1073/pnas.2108359118.