DNA damage response and repair pathways are important barriers to 
carcinogenesis. Here, we show that promyelocytic leukaemia (PML, also known as 
TRIM19), involved in sensing DNA damage and executing homologous recombination 
repair, is down-regulated in non-tumour liver cells surrounding hepatitis B 
virus (HBV)-related hepatocellular carcinoma (HCC). No PML mutation or deletion 
was found in HBV-infected liver or HCC cells. Immunohistochemical analysis of 
liver biopsies from patients with breast or liver cancer and HBV reactivation 
after chemotherapy revealed PML up-regulation and HBV exacerbation in normal 
liver tissue in response to DNA damage (functional PML), PML down-regulation in 
HCC peritumour cells associated with high HBsAg accumulation and low HBV 
replication activity (suppressive PML), and heterogeneous nuclear PML expression 
in HCC cells that lost HBV DNA and HBsAg and were non-reactive to DNA damage 
(dysregulated PML). Loss of PML in HBsAg-transgenic mice promoted chromosome 
breaks in liver cells and accelerated the accumulation of body and liver fat and 
the development of a liver steatosis-dysplasia-adenoma-carcinoma sequence in an 
inflammation-independent and male-predominant manner, compared to PML knock-out 
or HBsAg-transgenic mice during the same time period. These results indicate 
that PML deficiency facilitates genomic instability and promotes HBsAg-related 
hepatocarcinogenesis, which also involves androgen and lipid metabolism. These 
findings uncover a novel PML link between HBV-related tumourigenesis, DNA 
repair, and metabolism.