Biology subjects

Hwang, M.-S.

Publications and source records attributed to Hwang, M.-S..

2 recordsLinked to original sources

bioRxiv2020

Hypoxia-induced SETX links replication stress with the unfolded protein response

The levels of hypoxia associated with resistance to radiotherapy significantly impact cancer patient prognosis. These levels of hypoxia initiate a unique transcriptional response with the rapid activation of numerous transcription factors in a background of global repression of transcription. Here, we show that the biological response to radiobiological hypoxia includes the induction of the DNA/RNA helicase SETX. In the absence of hypoxia-induced SETX, R-loop levels increase, DNA damage accumulates, and DNA replication rates decrease. SETX plays a key role in protecting cells from DNA damage induced during transcription in hypoxia. Importantly, we show that the mechanism of SETX induction is reliant on the PERK/ATF4 arm of the unfolded protein response. These data not only highlight the unique cellular response to radiobiological hypoxia, which includes both a replication stress dependent DNA damage response and an unfolded protein response but uncover a novel link between these two distinct pathways.

cancer biology↗

bioRxiv2018

MAVS polymers smaller than 80 nm induce mitochondrial membrane remodeling and interferon signaling

Double-stranded RNA (dsRNA) is a potent proinflammatory signature of viral infection. Oligomerization of RIG-I-like receptors on cytosolic dsRNA nucleates self-assembly of the mitochondrial antiviral signaling protein (MAVS). In the current signaling model, the caspase recruitment domains of MAVS form helical fibrils that self-propagate like prions to promote signaling complex assembly. However, there is no conclusive evidence that MAVS forms fibrils in cells or with the transmembrane anchor present. We show here with super-resolution light microscopy that MAVS activation by dsRNA induces mitochondrial membrane remodeling. Quantitative image analysis at imaging resolutions as high as 32 nm shows that in the cellular context MAVS signaling complexes and the fibrils within them are smaller than 80 nm. The transmembrane domain of MAVS is required for its membrane remodeling, interferon signaling and proapoptotic activities. We conclude that membrane tethering of MAVS restrains its polymerization and contributes to mitochondrial remodeling and apoptosis upon dsRNA sensing.

molecular biology↗