Synergistic role of Ku80 and poly(ADP-ribose) polymerase in suppressing chromosomal aberrations and liver cancer formation.

摘要: Liver cancer is one of the major human tumors in world. Basic and epidemiological studies have proposed that risk factors for liver include alcohol diet as well infection with hepatitis B C viruses. However, mechanistic clues development this type largely unknown. Poly(ADP-ribose) polymerase (PARP-1) a component nonhomologous end-joining (NHEJ) machinery, Ku80, are two DNA end-binding molecules play multifunctional role damage signaling repair, recombination maintenance genomic stability. Here we show interaction PARP-1 Ku80 essential because PARP-1/Ku80 double null mice died at embryonic day (E) 9.5. Interestingly, haplo-insufficiency PARP-1−/− promotes hepatocellular adenoma carcinoma (HCC). These exhibited multistage tumor progression associated loss E-cadherin expression mutation β-catenin. Cytogenetic analysis revealed heterozygosity elevated chromosomal instability cells these harbored high degree aberrations including fragmentations, end-to-end fusions, recurrent nonreciprocal translocations (NRT). features reminiscent HCC. Taken together, data implicate synergistic function minimized chromosome suggest defects end-processing may be etiological HCC formation.