# SRSF3-TRIM28-MDC1 prevents DNA damage caused by R-loops in fatty liver disease in mice

## TL;DR

This study shows that the splicing factor SRSF3 prevents DNA damage in the liver, and its loss contributes to fatty liver disease and liver cancer.

## Contribution

The study identifies SRSF3 as a novel protector against DNA damage in liver disease by preventing R-loop accumulation.

## Key findings

- SRSF3 deletion in hepatocytes causes R-loop accumulation and DNA damage.
- Preventing SRSF3 degradation protects against DNA damage in MASH.
- SRSF3 forms a complex with TRIM28 and MDC1 to repair DNA damage.

## Abstract

Serine-rich splicing factor 3 (SRSF3) is crucial for the metabolic functions of the liver. The genetic deletion of SRSF3 in mouse hepatocytes impairs hepatic lipid and glucose metabolism and leads to fibrosis and formation of hepatocellular adenoma that progresses to hepatocellular carcinoma. SRSF3 protein is proteosomally degraded in metabolic-dysfunction associated fatty liver disease (MAFLD) and metabolic-dysfunction-associated steatohepatitis (MASH). We show here that depleting SRSF3 protein in hepatocytes promoted R-loop accumulation and increased DNA damage in the liver. Prevention of SRSF3 degradation in vivo protected hepatocytes from DNA double-strand breaks in mice with MASH. This protection extended to other DNA-damaging agents such as camptothecin, palmitic acid, or hydrogen peroxide when tested on HepG2 cells in vitro. SRSF3 interacted with TRIM28 and MDC1, which are components of the ATM DNA-damage repair complex, and knockdown of any of these 3 proteins reduced the expression of the other 2 proteins, suggesting they form a functional complex. Lastly, by preventing degradation of SRSF3, we were able to reduce tumors in a diethyl-nitrosamine–induced (DEN-induced) model of cirrhotic HCC. These findings suggest that maintenance of SRSF3 protein stability is crucial for preventing DNA damage and protecting liver from early metabolic liver disease and progression to HCC.

In this paper, the authors showed that loss of a splicing factor SRSF3 causes formation of R-loops and DNA damage that ultimately leads to liver cancer.