Aberrantly expressed HORMAD1 disrupts nuclear localization of MCM8–MCM9 complex and compromises DNA mismatch repair in cancer cells

• Published in: Cell death & disease 2020-07, Vol.11 (7), p.519-519, Article 519
• Main Authors: Liu, Kang, Wang, Yifan, Zhu, Quanfeng, Li, Peng, Chen, Jiyuan, Tang, Zhenghui, Shen, Yuanming, Cheng, Xiaodong, Lu, Lin-Yu, Liu, Yidan
• Format: Article
• Language: English
• Subjects: 631/337/1427/2121; 631/67/68; 82/29; 82/80; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Cancer; Cell Biology; Cell Culture; Cell Cycle Proteins - metabolism; Chromatin; Chromosomes; Deoxyribonucleic acid; DNA; DNA Mismatch Repair - genetics; DNA repair; Female; Genomic instability; Homologous recombination; Humans; Immunology; Life Sciences; Localization; Male; Meiosis; Mice; Mice, Knockout; Minichromosome Maintenance Proteins - genetics; Mismatch repair; MLH1 protein; Neoplasms - genetics; Prophase; Yeast
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-020-2736-1

HORMAD1 is a meiosis-specific protein that promotes synapsis and recombination of homologous chromosomes in meiotic prophase. Originally identified as a cancer/testis antigen, HORMAD1 is also aberrantly expressed in several cancers. However, the functions of HORMAD1 in cancer cells are still not clear. Here, we show that HORMAD1 is aberrantly expressed in a wide variety of cancers and compromises DNA mismatch repair in cancer cells. Mechanistically, HORMAD1 interacts with MCM8–MCM9 complex and prevents its efficient nuclear localization. As a consequence, HORMAD1-expressing cancer cells have reduced MLH1 chromatin binding and DNA mismatch repair defects. Consistently, HORMAD1 expression is associated with increased mutation load and genomic instability in many cancers. Taken together, our study provides mechanistic insights into HORMAD1’s functions in cancer cells, which can potentially be exploited for targeted therapy of HORMAD1-expressing cancers.