The impact of TOPBP1 mutations in human cancers on the DNA damage response

TOPBP1 (Topoisomerase IIβ-binding protein 1) mediates protein–protein interaction and DNA damage response (DDR) activation in DNA damage sensing and signaling to maintain genome integrity. However, the cancer-associated mutations of TOPBP1 have not been well studied. Here, 369 variants of TOPBP1 across 31 types of human cancer from three databases: The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC) and Catalogue of Somatic Mutations in Cancer (COSMIC), were analyzed. We found that six truncation mutations of TOPBP1 impaired its ability to repair DNA lesions and activate damage checkpoint, and ten missense mutations impaired the recruitment of TOPBP1 to DNA damage sites. Therefore, DNA damage repair capacity and cell cycle arrest in G2/M phase were disrupted. The structural modeling also confirms that missense mutations of TOPBP1 change the local spatial structure, which may further abolish the function of TOPBP1 in DDR. Taken together, our study reveals the functional defects of cancer-associated TOPBP1 mutations in DDR and may provide new therapy targets for cancer treatment.