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.

High-content imaging-based pooled CRISPR screens in mammalian cells

“…Six genes are involved in spindle function and chromosome segregation, which includes KIF11 ( Rapley et al, 2008 ), NUP62 ( Hashizume et al, 2013 ), SPDL1 ( Gassmann et al, 2008 ), and three core chromosomal passenger complex components INCENP , AURKB , and CDCA8 ( Terada, 2001 ; Carmena et al, 2012 ). Three genes function in DNA damage and repair, namely TICRR ( Sansam et al, 2010 ; Yu et al, 2019 ), TOP2A ( Bower et al, 2010 ; Yoshida and Azuma, 2016 ), and RAD51 ( Yoon et al, 2014 ; Sullivan and Bernstein, 2018 ), while the remaining four play roles in histone synthesis ( CASP8AP2 ; Sokolova et al, 2017 ), DNA maintenance ( DNA2 ; Duxin et al, 2009 ; Pawłowska et al, 2017 ), and cell cycle regulation ( SKA1 ; Sivakumar et al, 2014 , 2016 ; and FBXO5 ; Verschuren et al, 2007 ; Machida and Dutta, 2007 ; Data S3 ). Some of these functions might directly explain the larger nuclei phenotype after knockdown.…”

Increased Expression of TICRR Predicts Poor Clinical Outcomes: A Potential Therapeutic Target for Papillary Renal Cell Carcinoma

“…Uncontrollable DNA replication and thus cell proliferation are an essential mechanism in tumorigenesis. As a critical DNA replication regulator, TICRR plays an important role in several solid cancers ( Yu et al, 2019 ). In our study, we found that TICRR was significantly elevated in several urogenital cancers, including PRCC, chromophobe renal carcinoma, renal clear cell carcinoma, bladder urothelial carcinoma, cervical squamous cell carcinoma, and in endocervical adenocarcinoma.…”

“…Biologically, TICRR regulates the cell cycle via determining S-phase progression from the expression level to epigenetic control ( Charrasse et al, 2017 ; Maya-Mendoza et al, 2018 ) and thus promotes DNA replication. Overexpression of TICRR has been observed in several cancers, such as breast invasive carcinoma and liver hepatocellular carcinoma ( Yu et al, 2019 ). It is associated with tumorigenesis, resistance to chemotherapy, and poor clinical outcomes ( Yu et al, 2019 ).…”

“…Overexpression of TICRR has been observed in several cancers, such as breast invasive carcinoma and liver hepatocellular carcinoma ( Yu et al, 2019 ). It is associated with tumorigenesis, resistance to chemotherapy, and poor clinical outcomes ( Yu et al, 2019 ). However, the potential role and underlying mechanism of TICRR in PRCC is not clear yet.…”

High-content Imaging-based Pooled CRISPR Screens in Mammalian Cells

“…Six genes are involved in spindle function and chromosome segregation, which includes KIF11 26 , NUP62 27 , SPDL1 28 and three core chromosomal passenger complex (CPC) components INCENP, AURKB and CDCA8 29,30 . Three genes function in DNA damage and repair, namely TICRR 31,32 , TOP2A 33,34 and RAD51 35,36 , while the remaining four play roles in histone synthesis (CASP8AP2 37 ), DNA maintenance (DNA2 38,39 ) and cell cycle regulation (SKA1 40,41 and FBXO5 22,23 ) (Supplementary file 3). Some of these functions might directly explain the larger nuclei phenotype after knock down.…”