Dataset Information

TICRR Contributes to Tumorigenesis Through Accelerating DNA Replication in Cancers.

ABSTRACT: DNA replication is precisely regulated in cells and its dysregulation can trigger tumorigenesis. Here we identified that the TOPBP1 interacting checkpoint and replication regulator (TICRR) mRNA level was universally and highly expressed in 15 solid cancer types. Depletion of TICRR significantly inhibited tumor cell growth, colony formation and migration in vitro, and strikingly inhibited tumor growth in the xenograft model. We reveal that knockdown of TICRR inhibited not only the initiation but also the fork progression of DNA replication. Suppression of DNA synthesis by TICRR silencing caused DNA damage accumulation, subsequently activated the ATM/CHK2 dependent p53 signaling, and finally induced cell cycle arrest and apoptosis at least in p53-wild cancer cells. Further, we show that a higher TICRR level was associated with poorer overall survival (OS) and disease free survival (DFS) in multiple cancer types. In conclusion, our study shows that TICRR is involved in tumorigenesis by regulating DNA replication, acting as a common biomarker for cancer prognosis and could be a promising target for drug-development and cancer treatment.

SUBMITTER: Yu Q

PROVIDER: S-EPMC6591320 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

TICRR Contributes to Tumorigenesis Through Accelerating DNA Replication in Cancers.

Yu Qin Q Pu Shao-Yan SY Wu Huan H Chen Xiao-Qiong XQ Jiang Jian-Jun JJ Gu Kang-Shuyun KS He Yong-Han YH Kong Qing-Peng QP

Frontiers in oncology 20190618

DNA replication is precisely regulated in cells and its dysregulation can trigger tumorigenesis. Here we identified that the TOPBP1 interacting checkpoint and replication regulator (TICRR) mRNA level was universally and highly expressed in 15 solid cancer types. Depletion of TICRR significantly inhibited tumor cell growth, colony formation and migration in vitro, and strikingly inhibited tumor growth in the xenograft model. We reveal that knockdown of TICRR inhibited ...[more]

PMID: 31275851

Similar Datasets

Project description:UnlabelledEpstein-Barr virus (EBV) BKRF3 shares sequence homology with members of the uracil-N-glycosylase (UNG) protein family and has DNA glycosylase activity. Here, we explored how BKRF3 participates in the DNA replication complex and contributes to viral DNA replication. Exogenously expressed Flag-BKRF3 was distributed mostly in the cytoplasm, whereas BKRF3 was translocated into the nucleus and colocalized with the EBV DNA polymerase BALF5 in the replication compartment during EBV lytic replication. The expression level of BKRF3 increased gradually during viral replication, coupled with a decrease of cellular UNG2, suggesting BKRF3 enzyme activity compensates for UNG2 and ensures the fidelity of viral DNA replication. In immunoprecipitation-Western blotting, BKRF3 was coimmuno-precipitated with BALF5, the polymerase processivity factor BMRF1, and the immediate-early transactivator Rta. Coexpression of BMRF1 appeared to facilitate the nuclear targeting of BKRF3 in immunofluorescence staining. Residues 164 to 255 of BKRF3 were required for interaction with Rta and BALF5, whereas residues 81 to 166 of BKRF3 were critical for BMRF1 interaction in glutathione S-transferase (GST) pulldown experiments. Viral DNA replication was defective in cells harboring BKRF3 knockout EBV bacmids. In complementation assays, the catalytic mutant BKRF3(Q90L,D91N) restored viral DNA replication, whereas the leucine loop mutant BKRF3(H213L) only partially rescued viral DNA replication, coupled with a reduced ability to interact with the viral DNA polymerase and Rta. Our data suggest that BKRF3 plays a critical role in viral DNA synthesis predominantly through its interactions with viral proteins in the DNA replication compartment, while its enzymatic activity may be supplementary for uracil DNA glycosylase (UDG) function during virus replication.ImportanceCatalytic activities of both cellular UDG UNG2 and viral UDGs contribute to herpesviral DNA replication. To ensure that the enzyme activity executes at the right time and the right place in DNA replication forks, complex formation with other components in the DNA replication machinery provides an important regulation for UDG function. In this study, we provide the mechanism for EBV UDG BKRF3 nuclear targeting and the interacting domains of BKRF3 with viral DNA replication proteins. Through knockout and complementation approaches, we further demonstrate that in addition to UDG activity, the interaction of BKRF3 with viral proteins in the replication compartment is crucial for efficient viral DNA replication.

Dataset Information

TICRR Contributes to Tumorigenesis Through Accelerating DNA Replication in Cancers.

Publications

<i>TICRR</i> Contributes to Tumorigenesis Through Accelerating DNA Replication in Cancers.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets