Probing DNA damage repair
Cells missing the protein HMCES are hypersensitive to DNA-damaging agents that cause a common type of DNA lesion — an “abasic” site. But the agents also generate other types of lesions associated with mutations and cell lethality, making it unclear whether HMCES responds to abasic sites in cells.
David Cortez, PhD, and colleagues previously discovered the DNA repair mechanism initiated by HMCES. Now, the investigators have used the enzyme APOBEC3A, which introduces abasic sites into replicating DNA, to directly explore a role for HMCES.
They found that HMCES-deficient cells are hypersensitive to nuclear APOBEC3A. They further showed that HMCES protects abasic sites from being converted into mutagenic breaks in the DNA and that it maintains progression of the DNA replication machinery. The findings, published June 2 in Cell Reports, provide direct evidence that HMCES responds to abasic sites in single-stranded DNA and shields the sites of damage to avoid mutations and maintain genome integrity.
Staph’s activation of blood clotting
Acute bacterial endocarditis — infection of the inner lining of the heart — is most often caused by the bacteria Staphylococcus aureus (“staph”) and has up to a 40% mortality rate. Staph bacteria circulating in the blood adhere to heart valves and secrete the virulence factor staphylocoagulase (SC), which
activates the clotting factor prothrombin to build clot-like “vegetations” on the valves. A previous structural study indicated that the first few N-terminal amino acids in the SC protein insert into a pocket of prothrombin. Ashoka Maddur, PhD, Ingrid Verhamme, PhD, and colleagues have now characterized a series of SC fragments with changes in the N-terminal amino acids. They found SC variants that activated prothrombin with similar and higher efficiency compared to wild-type SC and defined the structural requirements of the prothrombin binding pocket.
The findings, reported in the Journal of Biological Chemistry, suggest that staph might change SC to evade the immune response and could guide efforts to develop antibody therapeutics targeted at SC.
Protecting the injured kidney
The proximal tubule — part of the kidney’s nephron — is a target of acute kidney injury (AKI), and its response to injury determines whether the kidney undergoes repair or progresses to chronic kidney disease (CKD).
Studies have suggested that Wnt/beta-catenin signaling, which increases after kidney injury, promotes fibrosis and CKD. Now, Leslie Gewin, MD, and colleagues have turned that conventional dogma on its head.
Using a genetic system, they specifically activated beta-catenin in mouse proximal tubules and showed that it protected mice from kidney
fibrosis and epithelial injury in two different models of AKI to CKD progression. They found that the protective effect required the presence of the transcription factor FoxO3, and they identified the protein CSE as a target of beta-catenin/ FoxO3.
The study, reported in the journal JCI Insight, is the first to increase beta-catenin specifically in proximal tubule cells, the authors note. The findings suggest that CSE may have therapeutic potential for CKD.