Deficiency in mammalian STN1 promotes colon cancer development via inhibiting DNA repair.
Dinh Duc NguyenEugene KimNhat Thong LeXianzhong DingRishi Kumar JaiswalRaymond Joseph KostlanThi Ngoc Thanh NguyenOlga ShivaMinh Thong LeWeihang ChaiPublished in: Science advances (2023)
Despite the high lethality of colorectal cancers (CRCs), only a limited number of genetic risk factors are identified. The mammalian ssDNA-binding protein complex CTC1-STN1-TEN1 protects genome stability, yet its role in tumorigenesis is unknown. Here, we show that attenuated CTC1/STN1 expression is common in CRCs. We generated an inducible STN1 knockout mouse model and found that STN1 deficiency in young adult mice increased CRC incidence, tumor size, and tumor load. CRC tumors exhibited enhanced proliferation, reduced apoptosis, and elevated DNA damage and replication stress. We found that STN1 deficiency down-regulated multiple DNA glycosylases, resulting in defective base excision repair (BER) and accumulation of oxidative damage. Collectively, this study identifies STN1 deficiency as a risk factor for CRC and implicates the previously unknown STN1-BER axis in protecting colon tissues from oxidative damage, therefore providing insights into the CRC tumor-suppressing mechanism.
Keyphrases
- dna repair
- dna damage
- risk factors
- binding protein
- mouse model
- signaling pathway
- young adults
- oxidative stress
- poor prognosis
- replacement therapy
- gene expression
- adipose tissue
- endoplasmic reticulum stress
- circulating tumor cells
- metabolic syndrome
- single molecule
- skeletal muscle
- cell cycle arrest
- wild type
- high fat diet induced