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The Role of Damaged DNA Binding Protein 2 in Colon Cancer

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posted on 08.02.2018 by Shuo Huang
Deregulation of the Wnt/β-catenin signaling pathway drives the development of colorectal cancer (CRC) but understanding of this pathway remains incomplete. Here we report that the damage-specific DNA-binding protein DDB2 is critical for β-catenin-mediated activation of RNF43, which restricts Wnt-signaling by removing Wnt receptors from the cell surface. Reduced expression of DDB2 and RNF43 was observed in human hyperplastic colonic foci. DDB2 recruited EZH2 and β-catenin at an upstream site in the Rnf43 gene, enabling functional interaction with distant TCF4/β-catenin binding sites in the intron of Rnf43. This novel activity of DDB2 was required for RNF43 function as a negative feedback regulator of Wnt-signaling. Mice genetically deficient in DDB2 exhibited increased susceptibility to colon tumor development in a manner associated with higher abundance of the Wnt receptor-expressing cells and greater activation of the downstream Wnt-pathway. Our results identify DDB2 as both a partner and regulator of Wnt-signaling with an important role in suppressing colon cancer development.

History

Advisor

Raychaudhuri, Pradip

Chair

Raychaudhuri, Pradip

Department

Biochemistry and Molecular Genetics

Degree Grantor

University of Illinois at Chicago

Degree Level

Doctoral

Committee Member

Merrill, Bradley Hay, Nissim Tyner, Angela Rong, Lijun

Submitted date

December 2017

Issue date

03/10/2017

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