DNA damage prompts DNA repair that may be either slapdash or tidy, depending on the circumstances. For example, during the S and G2 phases of the cell cycle, the BRCA1 protein promotes the tidy sort of repair, error-free homologous recombination (HR). Presumably, HR occurs during the S and G2 phases because these are the times when sister chromatids stay together. If a double-strand DNA break should occur on one chromatid, a repair template is available on the other chromatid. Although this mechanism seems plausible, its workings have not been described in detail.
New specifics about the activation of error-free DNA repair have been uncovered by scientists based at the University of Copenhagen. These scientists, led by Anja Groth, PhD, professor at the Biotech Research and Innovation Center at the University of Copenhagen, reported that a protein must recognize a histone so that the BRCA1 protein can accumulate at double-strand breaks and promote HR, rather than allow repair by the error-prone non-homologous end-joining mechanism, which merely “glues” cut DNA strands together without the benefit of a repair template.
The new findings appeared recently in the journal Nature Cell Biology, in an article titled, “H4K20me0 recognition by BRCA1–BARD1 directs homologous recombination to sister chromatids.” Essentially, this article demonstrates that BRCA1 recruitment requires recognition of histone H4 unmethylated at lysine 20 (H4K20me0), linking DSB repair pathway choice directly to sister chromatid availability.
“We identify the ankyrin repeat domain of BRCA1-associated RING domain protein 1 (BARD1)—the obligate BRCA1 binding partner3—as a reader of H4K20me0 present on new histones in post-replicative chromatin,” the article’s authors wrote. “BARD1 ankyrin repeat domain mutations disabling H4K20me0 recognition abrogate accumulation of BRCA1 at DSBs, causing aberrant build-up of 53BP1, and allowing anti-resection activity to prevail in S and G2.”
BARD1 has been known to work like a so-called tumor suppressor. But now it is apparent that BARD1 also has a scanning function that tells the BRCA1 protein, and thus the cell, that the flawless repair system can be launched. If possible, it then launches the BRCA1 function that plays such a vital role in cancer protection.
‘You can say that BARD1 tells the cell that the flawless system can be launched, because BARD determines whether there are signs that the cell contains two identical DNA strings,” Groth explained. “If so, the ‘flawed’ repair system is blocked, while the flawless system is launched.
“You can imagine that the one repair system somewhat awkwardly tries to glue two DNA strings together, while the other system produces a 3D-printed copy resembling the DNA before damage completely. The first system produces far more errors than the latter, and therefore the latter provides far better protection against tumor development.
In connection with this and other discoveries, the researchers have founded the company Ankrin Therapeutics, which seeks to utilize DNA repair mechanisms to develop new targeted cancer treatment.