Independent of already known roles in impaired DNA repair, mutations in the Fanconi anemia pathway also disrupt cells’ antiviral immunity and removal of damaged mitochondria, resulting in an accumulation of mitochondrial reactive oxygen species.
Independent of already known roles in impaired DNA repair, mutations in the Fanconi anemia (FA) pathway also disrupt cells’ antiviral immunity and removal of damaged mitochondria, resulting in an accumulation of mitochondrial reactive oxygen species (ROS), according to authors of a study involving transgenic mice, published in the journal Cell.
The findings might help to explain FA patients’ increased risks of infection and cancers, the researchers suggested.
“Our findings suggest a novel mechanism by which mutations in FA genes may lead to the clinical manifestations in patients with FA anemia and to cancers in patients with mutations in FA genes,” study coauthor Rhea Sumpter, MD, PhD, of the Center for Autophagy Research at the University of Texas Southwestern Medical Center in Dallas, was quoted as saying in a press release. “We’ve shown that this new function of the FA genes in the selective autophagy pathways does not depend on their role in DNA repair.”
Mutations in any of 19 FA pathway genes occur in patients with FA as well as patients without FA who are diagnosed with familial breast or ovarian cancer. FA mutations are also implicated in congenital defects, blood disorders, and childhood leukemia.
The coauthors’ findings implicate mutations in FANCC, BRCA1 and BRCA2 (which are also known as FANCS and FANCD1), among other FA pathway genes. These mutations inhibit selective autophagy in cellular cytoplasm, impairing antiviral response and activating the ROS-associated “inflammasome,” the team showed. The affected genes normally orchestrate selective autophagy’s cytoplasmic virophagy and removal of damaged mitochondria (mitophagy).
The study team used genome-wide small interfering RNA (siRNA) screens to identify selective autophagy factors, and FANCC’s role in selective autophagy was validated using siRNA targeting of the gene in embryologic mouse fibroblasts, they reported. Subsequent in vitro and in vivo work with transgenic mice confirmed the FA pathway genes’ roles in virophagy and mitophagy, their role in the accumulation of mitochondrial ROS, and the independence of these functions from previously known nuclear DNA repair functions.
The findings might lead to new treatments for both FA and FA mutation-associated cancers, but more research is needed, the team cautioned.
“The finding that FA genes function in clearing mitochondria and decreasing inflammasome activation provides a potential new inflammasome-targeted avenue of therapy for patients with diseases related to mutations in the FA genes,” said coauthor Beth Levine, MD, Professor of Internal Medicine and of Microbiology, and a faculty member of the Center for Autophagy Research, at the University of Texas Southwestern Medical Center.
“The clearest therapeutic possibilities to come from our study results are the development of new FA agents that target the inflammasome and production of interleukin 1 beta (IL-1Î²), a pro-inflammatory cytokine,” speculated Dr. Sumpter. “Clinically, IL-1Î² signaling has been targeted with FDA-approved drugs very successfully in several autoinflammatory diseases that involve excessive inflammasome activation. Our results suggest that FA patients may also benefit from these therapies.”