RESUMO
Endonuclease VIII-like 3 (NEIL3) is a versatile DNA glycosylase that repairs a diverse array of chemical modifications to DNA. Unlike other glycosylases, NEIL3 has a preference for lesions within single-strand DNA and at single/double-strand DNA junctions. Beyond its canonical role in base excision repair of oxidized DNA, NEIL3 initiates replication-dependent interstrand DNA crosslink repair as an alternative to the Fanconi Anemia pathway. This review outlines our current understanding of NEIL3's biological functions, role in disease, and three-dimensional structure as it pertains to substrate specificity and catalytic mechanism.
Assuntos
DNA Glicosilases , Reparo do DNA , Humanos , DNA Glicosilases/metabolismo , DNA Glicosilases/química , Especificidade por Substrato , DNA/metabolismo , Dano ao DNA , Animais , Replicação do DNA , N-Glicosil HidrolasesRESUMO
The cytokine IFNγ differentially impacts on tumors upon immune checkpoint blockade (ICB). Despite our understanding of downstream signaling events, less is known about regulation of its receptor (IFNγ-R1). With an unbiased genome-wide CRISPR/Cas9 screen for critical regulators of IFNγ-R1 cell surface abundance, we identify STUB1 as an E3 ubiquitin ligase for IFNγ-R1 in complex with its signal-relaying kinase JAK1. STUB1 mediates ubiquitination-dependent proteasomal degradation of IFNγ-R1/JAK1 complex through IFNγ-R1K285 and JAK1K249. Conversely, STUB1 inactivation amplifies IFNγ signaling, sensitizing tumor cells to cytotoxic T cells in vitro. This is corroborated by an anticorrelation between STUB1 expression and IFNγ response in ICB-treated patients. Consistent with the context-dependent effects of IFNγ in vivo, anti-PD-1 response is increased in heterogenous tumors comprising both wildtype and STUB1-deficient cells, but not full STUB1 knockout tumors. These results uncover STUB1 as a critical regulator of IFNγ-R1, and highlight the context-dependency of STUB1-regulated IFNγ signaling for ICB outcome.