7 research outputs found
SUMOylation promotes protective responses to DNA-protein crosslinks
DNA-protein crosslinks (DPCs) are highly cytotoxic lesions that
obstruct essential DNA transactions and whose resolution is critical for cell and organismal fitness. However, the mechanisms by
which cells respond to and overcome DPCs remain incompletely
understood. Recent studies unveiled a dedicated DPC repair pathway in higher eukaryotes involving the SprT-type metalloprotease
SPRTN/DVC1, which proteolytically processes DPCs during DNA
replication in a ubiquitin-regulated manner. Here, we show that
chemically induced and defined enzymatic DPCs trigger potent
chromatin SUMOylation responses targeting the crosslinked
proteins and associated factors. Consequently, inhibiting SUMOylation compromises DPC clearance and cellular fitness. We demonstrate that ACRC/GCNA family SprT proteases interact with SUMO
and establish important physiological roles of Caenorhabditis elegans GCNA-1 and SUMOylation in promoting germ cell and
embryonic survival upon DPC formation. Our findings provide first
global insights into signaling responses to DPCs and reveal an
evolutionarily conserved function of SUMOylation in facilitating
responses to these lesions in metazoans that may complement
replication-coupled DPC resolution processes
Cartilage immunoprivilege depends on donor source and lesion location
The ability to repair damaged cartilage is a major goal of musculoskeletal tissue engineering. Allogeneic (same species, different individual) or xenogeneic (different species) sources can provide an attractive source of chondrocytes for cartilage tissue engineering, since autologous (same individual) cells are scarce. Immune rejection of non-autologous hyaline articular cartilage has seldom been considered due to the popular notion of “cartilage immunoprivilege.” The objective of this study was to determine the suitability of allogeneic and xenogeneic engineered neocartilage tissue for cartilage repair. To address this, scaffold-free tissue engineered articular cartilage of syngeneic (same genetic background), allogeneic, and xenogeneic origin were implanted into two different locations of the rabbit knee (n=3 per group/location). Xenogeneic engineered cartilage and control xenogeneic chondral explants provoked profound innate inflammatory and adaptive cellular responses, regardless of transplant location. Cytological quantification of immune cells showed that, while allogeneic neocartilage elicited an immune response in the patella, negligible responses were observed when implanted into the trochlea; instead the responses were comparable to microfracture-treated empty defect controls. Allogeneic neocartilage survived within the trochlea implant site and demonstrated graft integration into the underlying bone. In conclusion, the knee joint cartilage does not represent an immune privileged site, strongly rejecting xenogeneic but not allogeneic chondrocytes in a location-dependent fashion. This difference in location-dependent survival of allogeneic tissue may be associated with proximity to the synovium