Cancer genome sequencing projects have identified hundreds of genetic 
alterations, often at low frequencies, raising questions as to their functional 
relevance. One exemplar gene is HUWE1, which has been found to be mutated in 
numerous studies. However, due to the large size of this gene and a lack of 
functional analysis of identified mutations, their significance to 
carcinogenesis is unclear. To determine the importance of HUWE1, we chose to 
examine its function in colorectal cancer, where it is mutated in up to 15 per 
cent of tumours. Modelling of identified mutations showed that they inactivate 
the E3 ubiquitin ligase activity of HUWE1. Genetic deletion of Huwe1 rapidly 
accelerated tumourigenic in mice carrying loss of the intestinal tumour 
suppressor gene Apc, with a dramatic increase in tumour initiation. 
Mechanistically, this phenotype was driven by increased MYC and rapid DNA damage 
accumulation leading to loss of the second copy of Apc The increased levels of 
DNA damage sensitised Huwe1-deficient tumours to DNA-damaging agents and to 
deletion of the anti-apoptotic protein MCL1. Taken together, these data identify 
HUWE1 as a bona fide tumour suppressor gene in the intestinal epithelium and 
suggest a potential vulnerability of HUWE1-mutated tumours to DNA-damaging 
agents and inhibitors of anti-apoptotic proteins.