Abstract
Fanconi anemia (FA) patients are highly susceptible to solid tumors at multiple anatomical sites including head and neck region. A subset of head and neck cancers (HNCs) is associated with ‘high-risk’ HPVs, particularly HPV16. However, the correlation between HPV oncogenes and cancers in FA patients is still unclear. We previously learned that FA deficiency in mice predisposes HPV16 E7 transgenic mice to HNCs. To address HPV16 E6’s oncogenic potential under FA deficiency in HNCs, we utilized HPV16 E6-transgenic mice (K14E6) and HPV16 E6/E7-bi-transgenic mice (K14E6E7) on genetic backgrounds sufficient or deficient for one of the fanc genes, fancD2 and monitored their susceptibility to HNCs. K14E6 mice failed to develop tumor. However, E6 and fancD2-deficiency accelerated E7-driven tumor development in K14E6E7 mice. The increased tumor incidence was more correlated with E7-driven DNA damage than proliferation. We also found that deficiency of pocket proteins, pRb, p107, and p130 that are well-established targets of E7, could recapitulate E7’s induction of DNA damage. Our findings support the hypothesis that E7 induces HPV-associated HNCs by promoting DNA damage through the inactivation of pocket proteins, which explains why a deficiency in DNA damage repair would increase susceptibility to E7-driven cancer. Our results further demonstrate the unexpected finding that FA deficiency does not predispose E6 transgenic mice to HNCs, indicating a specificity in the synergy between FA deficiency and HPV oncogenes in causing HNCs.
Highlights
Fanconi Anemia (FA), which is a rare heterogeneous and recessive genetic disease, displayed developmental defects and abnormalities in hematopoietic stem cells such as bone marrow failure and acute myeloid leukemia, the major phenotypes displayed in early childhood of the patients
To address the role of E6 and deficiency of the FA pathway in head and neck carcinogenesis, HPV type-16 (HPV16) E6 transgenic (K14E6) and HPV16 E7 transgenic (K14E7) mice were crossed to fancD2-null mice to generate four different genotypes; K14E6/FancD2+/+, K14E6/FancD2-/, K14E6E7/FancD2+/+, and K14E6E7/FancD2-/- mice
In this study we provide experimental evidence that FA deficiency increases the susceptibility of mice expressing both the HPV16 E6 and E7 oncogenes to the development of head and neck cancer, but not in mice just expressing E6
Summary
Fanconi Anemia (FA), which is a rare heterogeneous and recessive genetic disease, displayed developmental defects and abnormalities in hematopoietic stem cells such as bone marrow failure and acute myeloid leukemia, the major phenotypes displayed in early childhood of the patients. The mono-ubiquitinated FancD2/I are localized to sites of DNA damage where they interact with other proteins known to be involved in repairing the damaged DNA, such as BRCA1, FancD1/BRCA2, FancN/PALB2 and Rad leading to DNA repair [3,4]. Disruption of this FA pathway leads to increased sensitivity to DNA cross-linkers, chromosomal instability, spontaneous sister chromatid exchange, and cell cycle perturbations [5,6]. Mono-ubiquitination of FancD2 is critical for its chromatin localization and acting as a scaffold for specific DNA repair factors. Depletion of FancD2 inhibits HR response, indicating that HR acts downstream of FancD2
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