A relatively enormous ‘protein scaffolding’ network that stabilizes and then fixes DNA damage was found to be a potential cause of cancer by a team of scientists in Denmark if the mechanism utilizing the proteins 53BP1 and RIF1 malfunctions. The resulting pathway could be the culprit behind some diseases, according to the results reported in the journal Nature.
The new finding is a “unique discovery,” further extending scientific knowledge of the body’s natural defense mechanisms—and where they may go wrong, according to Jiri Lukas, the lead author, of the Novo Nordisk Foundation Center for Protein Research at the University of Copenhagen in Denmark.
“This opens up an opportunity to better (understand) how DNA damage causes disease and design drugs that improve treatment of patients with unstable DNA,” said Lukas.
The observations at minute levels were made with super-resolution microscopy, investigators wrote. The hardware included an ELYRA PS.1 microscope system (Zeiss) and a DeltaVision OMX V3 Blaze system (GE Healthcare).
The mammalian cells mobilize neighboring chromatin to shield the DNA ends against extra cuts which could undermine repair and reconstruction effort. The work is overseen by 53BP1, according to the scientists. The 53BP1 accumulates at the site of double-strand breaks of DNA triggers RIF1 and also the shieldin-CST-POL alpha complex.
The 53BP1 and RIF1 alternately pile up, creating an ordered, circular, 3-dimensional arrangement, according to the findings. The structure, compared to the size of the DNA break, is like a basketball surrounding the head of a pin.
“This could be compared to putting a plaster cast on a broken leg,” said Fena Ochas, a Novo Nordisk postdoctoral candidate who is also the first author. “It stabilizes the fracture and prevents the damage from getting worse and reaching a point where it can no longer heal.”
The large structure then molecularly attracts the aforementioned “shieldin network,” described in the journal Cell last year by some of the members of the same Novo Nordisk team.
But the breakdown of the whole natural repair system, which could underlie cancer, could start at the beginning or the profess, according to the latest paper. The depletion of 53BP1 or RF1 “disrupts this arrangement and leads to decompaction of DSB-flanking chromatin, reduction in the interchromatin space, aberrant spreading of DNA repair proteins, and hyper-resection,” among other major process breakdowns.
1. Ochs F, Karemore G, Miron E, et al. Stabilization of chromatin topology safeguards genome integrity. Nature. 2019 Oct;574(7779):571-574. doi: 10.1038/s41586-019-1659-4. Epub 2019 Oct 23.
2. Gupta R, Somyajit Y, Narita T, et al. DNA Repair Network Analysis Reveals Shieldin as a Key Regulator of NHEJ and PARP Inhibitor Sensitivity. Cell. 2018 May 3;173(4):972-988.e23. doi: 10.1016/j.cell.2018.03.050. Epub 2018 Apr 12.