Abstract
TNKS1BP1 is a member of the poly(ADP‐ribose) polymerase (PARP) superfamily. Our previous studies have demonstrated that TNKS1BP1 plays an important role in DNA damage response. But whether and how TNKS1BP1 associates with cancer is still not clear. Here, we found that TNKS1BP1 was upregulated in human lung adenocarcinoma (LAC) tissues, and was associated with poor overall survival (OS) in LAC patients. Dysregulation of TNKS1BP1 affected the sensitivity of A549 cells to several DNA damage agents including cisplatin, bleomycin, and ionizing radiation. Mechanically, overexpression of TNKS1BP1 increased the accumulation of S phase cells, which was accompanied by a decrease in M phase cells. More importantly, we found TNKS1BP1 regulated genome stability, mainly through affecting the homologous recombination pathway of DNA double‐strand breaks by inhibiting the RAD51 foci formation. Overall, our study indicates that, in LAC, aberrant expressions of TNKS1BP1 are common events, and overexpression of TNKS1BP1 might affect outcomes of cancer patients to chemotherapy and radiotherapy.
Highlights
TNKS1BP1, a tankyrase 1 binding protein 1 of 182 kDa, named TAB 182, has been identified in a yeast two-hybrid experiment as a binding protein of tankyrase 1, which was found to poly(ADP-ribosyl)ate TNKS1BP1 in vitro
Primary antibodies used in this study were as follows: anti-TNKS1BP1, anti-CtIP and BRCA1 (Santa Cruz), anti- TNKS1BP1, anti-Ku70 and RAD51 (Gene Tex), Anti-pH3 and anti-γH2AX (Millipore), anti-53BP1 (Cell Signalling Technology). homologous recombination (HR) and Nonhomologous end joining (NHEJ) reporter plasmids were gifted by Dr Zhenkun Lou (Division of Oncology Research, Mayo Clinic Rochester, USA)
To assess whether TNKS1BP1 plays an important role in cancer development, we analyzed TNKS1BP1 expression pattern in the lung cancer and ovarian cancer at genomic level based on the public database
Summary
TNKS1BP1, a tankyrase 1 binding protein 1 of 182 kDa, named TAB 182, has been identified in a yeast two-hybrid experiment as a binding protein of tankyrase 1, which was found to poly(ADP-ribosyl)ate TNKS1BP1 in vitro. TNKS1BP1 Regulates the HR Pathway containing a RXXPDG motif [1] that is necessary and sufficient for tankyrase binding. TNKS1BP1 localizes to cytoplasm in which it co-stains with the cortical actin network and nucleus in a heterochromatic staining pattern. Previous studies have demonstrated that TNKS1BP1 functions in both telomere maintenance and DNA damage response. TNKS1BP1 can compete with TRF1 to link the multiple binding site of tankyrase which potentially interferes with the transport of tankyrase 1 from cytoplasm to nucleus and the location in telomeres, affecting the stability of telomeres [2, 3]. TNKS1BP1 expression could be upregulated by γ-ray irradiation, and depletion of TNKS1BP1 was found to sensitize HeLa cells to the ionizing radiation (IR)[4].whether TNKS1BP1 functions in tumorigenesis and cancer cellular response to radiation and chemotherapy is still unclear
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