Overlooked FANCD2 variant encodes a promising, portent tumor suppressor, and alternative polyadenylation contributes to its expression.
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.
University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI, USA.
Bing
B
Han
University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI, USA.
Yihang
Y
Shen
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Piyan
P
Zhang
University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI, USA.
Panneerselvam
P
Jayabal
University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI, USA.|Graduate Program of Molecular Biosciences and Bioengineering, University of Hawaii, Honolulu, HI, USA.
Raymond
R
Che
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Jun
J
Zhang
University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI, USA.
Herbert
H
Yu
University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI, USA.|Graduate Program of Molecular Biosciences and Bioengineering, University of Hawaii, Honolulu, HI, USA.
Peiwen
P
Fei
D017398:Alternative Splicing; D014408:Biomarkers, Tumor / Q000235:genetics*; D063646:Carcinogenesis / Q000235:genetics; D005199:Fanconi Anemia / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D026723:Polyadenylation / Q000235:genetics; D059467:Transcriptome; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology
D014408:Biomarkers, Tumor; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D025521:Tumor Suppressor Proteins
FANCD2; FANCD2-V1; fanconi anemia; polyadenylation site (PAS); tumor suppressor