Sall4 won’t give stem cells a break

A protein that helps embryonic stem cells (ESCs) retain their identity also induces the cells to repair DNA damage, Xiong et al. report.

Fixing broken DNA is particularly important for ESCs because they pass on any mutations to their differentiated descendants. Mouse ESCs are adept at making repairs—they carry far fewer mutations than do differentiated cells—but how they achieve this isn’t clear. Previous studies have revealed that double-strand breaks (DSBs) trigger epigenetic changes to ESC chromatin. Xiong et al. tested whether the protein Sall4, which suppresses differentiation of ESCs and interacts with chromatin-remodeling protein complexes, has a role in DNA repair.

The researchers found that ESCs lacking Sall4 were poor at mending DSBs. Sall4 relocated to the sites of these breaks and activated ATM, a kinase that signals DNA damage and instigates repair. Sall4 associated with Rad50, a component of the MRN complex that recruits ATM to the damage sites and turns the kinase on. The findings suggest that Sall4 either draws the MRN complex to DSBs or stabilizes the complex at these locations, thus allowing it to activate ATM.

Xiong et al. determined that Baf60a recruits Sall4 to DSBs. Baf60a is a component of the SWI/SNF complex that reorganizes chromatin at sites of DNA damage. The study raises the possibility that Sall4 performs the same role in cancer cells as it does in ESCs. Tumor cells often overexpress the protein, suggesting that it might help them fix DNA damage and survive chemotherapy.