Convergence of Rad6/Rad18 and Fanconi anemia tumor suppressor pathways upon DNA damage.
Extremely high cancer incidence associated with patients with Fanconi anemia (FA) suggests the importance of the FA signaling pathway in the suppression of non-FA human tumor development. Indeed, we found that an impaired FA signaling pathway substantially contributes to the development of non-FA human tumors. However, the mechanisms underlying the function of the FA pathway remain less understood. Using RNA interfering approach in combining with cell proliferation and reporter assays, we showed that the function of FA signaling pathway is at least partly mediated through coupling with hRad6/hRad18 signaling (HHR6 pathway). We previously reported that FANCD2 monoubiquitination, a hallmark of the FA pathway activation, can be regulated by HHR6. Here we found that hRad18 can also regulate activation of the FA pathway. More importantly, we found that FANCD2 is capable of modulating activity of DNA translesion synthesis polymerase eta, an effector of HHR6 pathway. These results provide novel insights into how the FA pathway is intertwined with HHR6 pathway to maintain chromosomal stability and suppress the development of human cancer, representing an important conceptual advance in the field of FA cancer research.
Park
Hwan Ki
HK
The Hormel Institute, University of Minnesota, Austin, Minnesota, United States of America.
Wang
Hong
H
Zhang
Jun
J
Datta
Suvamoy
S
Fei
Peiwen
P
D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D005199:Fanconi Anemia / Q000235:genetics* / Q000378:metabolism; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D034622:RNA Interference; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination; D000099270:Y-Family DNA Polymerases
D004268:DNA-Binding Proteins; D004259:DNA-Directed DNA Polymerase; D052236:Fanconi Anemia Complementation Group D2 Protein; D044767:Ubiquitin-Protein Ligases; C485954:RAD18 protein, human; C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases