2 research outputs found
BRAT1 links Integrator and defective RNA processing with neurodegeneration
Mutations in BRAT1, encoding BRCA1-associated ATM activator 1, have been associated with neurodevelopmental and neurodegenerative disorders characterized by heterogeneous phenotypes with varying levels of clinical severity. However, the underlying molecular mechanisms of disease pathology remain poorly understood. Here, we show that BRAT1 tightly interacts with INTS9/INTS11 subunits of the Integrator complex that processes 3’ ends of various noncoding RNAs and pre-mRNAs. We find that Integrator functions are disrupted by BRAT1 deletion. In particular, defects in BRAT1 impede proper 3’ end processing of UsnRNAs and snoRNAs, replication-dependent histone pre-mRNA processing, and alter the expression of protein-coding genes. Importantly, impairments in Integrator function are also evident in patient-derived cells from BRAT1 related neurological disease. Collectively, our data suggest that defects in BRAT1 interfere with proper Integrator functions, leading to incorrect expression of RNAs and proteins, resulting in neurodegeneration.</p
Two-Step Mechanism of Cellular Uptake of Cationic Gold Nanoparticles Modified by (16-Mercaptohexadecyl)trimethylammonium Bromide
Cationic
colloidal gold nanorods (GNRs) have a great potential
as a theranostic tool for diverse medical applications. GNRs’
properties such as cellular internalization and stability are determined
by physicochemical characteristics of their surface coating. GNRs
modified by (16-mercaptohexadecyl)Âtrimethylammonium bromide (MTAB), <sup>MTAB</sup>GNRs, show excellent cellular uptake. Despite their promise
for biomedicine, however, relatively little is known about the cellular
pathways that facilitate the uptake of GNRs, their subcellular fate
and intracellular persistence. Here we studied the mechanism of cellular
internalization and long-term fate of GNRs coated with MTAB, for which
the synthesis was optimized to give higher yield, in various human
cell types including normal diploid versus cancerous, and dividing
versus nondividing (senescent) cells. The process of <sup>MTAB</sup>GNRs internalization into their final destination in lysosomes proceeds
in two steps: (1) fast passive adhesion to cell membrane mediated
by sulfated proteoglycans occurring within minutes and (2) slower
active transmembrane and intracellular transport of individual nanorods
via clathrin-mediated endocytosis and of aggregated nanorods via macropinocytosis.
The expression of sulfated proteoglycans was the major factor determining
the extent of uptake by the respective cell types. Upon uptake into
proliferating cells, <sup>MTAB</sup>GNRs were diluted equally and
relatively rapidly into daughter cells; however, in nondividing/senescent
cells the loss of <sup>MTAB</sup>GNRs was gradual and very modest,
attributable mainly to exocytosis. Exocytosed <sup>MTAB</sup>GNRs
can again be internalized. These findings broaden our knowledge about
cellular uptake of gold nanorods, a crucial prerequisite for future
successful engineering of nanoparticles for biomedical applications
such as photothermal cancer therapy or elimination of senescent cells
as part of the emerging rejuvenation approach