Abstract
AbstractType I/II interferons (IFNα,β/IFNɣ) are cytokines that activate signal-transducer-and-activator-of-transcription-1 (STAT1). The STAT1 N-terminal domain (NTD) mediates dimerization and cooperative DNA-binding. The STAT1 DNA-binding domain (DBD) confers sequence-specific DNA-recognition. STAT1 has been connected to growth inhibition, replication stress and DNA-damage. We investigated how STAT1 and NTD/DBD mutants thereof affect fibrosarcoma cells. STAT1 and indicated mutants do not affect proliferation of resting and IFNα-treated cells as well as checkpoint kinase signaling, and phosphorylation of the tumor-suppressive transcription factor p53 ensuing ɣ-irradiation. Of the STAT1 reconstituted U3A cells those with STAT1 NTD mutants accumulate the highest levels of the replication stress/DNA-damage marker S139-phosphorylated histone H2AX (ɣH2AX). This is similarly seen with a STAT1 NTD/DBD double mutant, indicating transcription-independent effects. Furthermore, U3A cells with STAT1 NTD mutants are most susceptible to apoptotic DNA fragmentation and cleavage of the DNA repair protein PARP1. These data provide novel insights into the relevance of the STAT1 NTD.
Highlights
Binding of cytokines and growth hormones to cognate receptors activates the inducible transcription factors STAT1,2,3,4,5A,5B,6
We investigated how STAT1 and N-terminal domain (NTD)/DNA-binding domain (DBD) mutants thereof affect fibrosarcoma cells
U3A cells with STAT1 NTD mutants are most susceptible to apoptotic DNA fragmentation and cleavage of the DNA repair protein PARP1
Summary
Binding of cytokines and growth hormones to cognate receptors activates the inducible transcription factors STAT1,-2,-3,-4,-5A,-5B,-6. STATs have a modular structure (NTD, coiled-coil, DBD, linker, SH2-domain, p-tyrosine site, C-terminal activation domain) (Khodarev et al, 2012; Wieczorek et al, 2012). IFN-/STAT1-related signatures promote resistance to chemotherapy and ɣ-irradiation in cancer cells (Ah-Koon et al, 2016; Kaowinn et al, 2017; Khodarev et al, 2012; Malilas et al, 2013). STAT1 can though promote sensitivity to DNA crosslinking agents (Prieto-Remon et al, 2013) and proapoptotic gene expression (Khodarev et al, 2012; Wieczorek et al, 2012). Modulators of STAT1 may be novel and innovative context-dependent anti-cancer drugs (Khodarev et al, 2012)
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