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Overlooked FANCD2 variant encodes a promising, portent tumor suppressor, and alternative polyadenylation contributes to its expression
- Source :
- Oncotarget
- Publication Year :
- 2017
- Publisher :
- Impact Journals, LLC, 2017.
-
Abstract
- Fanconi Anemia (FA) complementation group D2 protein (FANCD2) is the center of the FA tumor suppressor pathway, which has become an important field of investigation in human aging and cancer. Here we report an overlooked central player in the FA pathway, FANCD2 variant 2 (FANCD2-V2), which appears to perform more potent tumor suppressor-function compared to the known variant of FANCD2, namely, FANCD2-V1. Detailed analysis of the FANCD2 gene structure indicated a proximal and distal polyadenylation site (PAS), associated with V2 and V1 transcripts accordingly. RNA polymerase II Chromatin immunoprecipitation (ChIP) targeting the two PAS-regions determined lesser binding of RNA pol II to DNA fragments in the distal PAS region in non-malignant cells compared to malignant cells. Conversely, the opposite occurred in the proximal PAS region. Moreover, RNA immunoprecipitation (RIP) identified that U2 snRNP, a major component of RNA splicing complex that interacts with the 3'end of an intron, showed greater binding to the last intron of the FANCD2-V1 transcript in malignant cells compared to the non-malignant cells. Importantly, our data showed that in human tissue samples, the ratio of V2 /V1 expression in lung, bladder, or ovarian cancer correlates inversely with the tumor stages/grades. Therefore, these findings provide a previously unrecognized central player FANCD2-V2 and thus novel insights into human tumorigenesis, and indicate that V2/V1 can act as an effective biomarker in assisting the recognition of tumor malignance.
- Subjects :
- 0301 basic medicine
congenital, hereditary, and neonatal diseases and abnormalities
Lung Neoplasms
Polyadenylation
tumor suppressor
Carcinogenesis
RNA polymerase II
medicine.disease_cause
03 medical and health sciences
0302 clinical medicine
hemic and lymphatic diseases
Biomarkers, Tumor
medicine
Humans
Neoplasm Staging
Ovarian Neoplasms
Genetics
Regulation of gene expression
biology
FANCD2
Fanconi Anemia Complementation Group D2 Protein
Tumor Suppressor Proteins
Alternative splicing
FANCD2-V1
Intron
nutritional and metabolic diseases
Molecular biology
3. Good health
Alternative Splicing
Fanconi Anemia
030104 developmental biology
Gene Expression Regulation
Urinary Bladder Neoplasms
Oncology
polyadenylation site (PAS)
030220 oncology & carcinogenesis
RNA splicing
biology.protein
Female
Transcriptome
Chromatin immunoprecipitation
Research Paper
Subjects
Details
- ISSN :
- 19492553
- Volume :
- 8
- Database :
- OpenAIRE
- Journal :
- Oncotarget
- Accession number :
- edsair.doi.dedup.....f77d5c80b29a8184fe725ad146432bba