Patrick Sung, Ph.D.; Hengyao Niu, Ph.D.
NIEHS Grants K99ES021441, R01ES007061
NIEHS grantees found that Srs2 and Exo1 enzymes act together to prevent and repair mistakes made during DNA replication in yeast cells. Many essential cellular functions are conserved between yeast and people, so it is likely a similar DNA repair process may operate in people. The results have implications for understanding Aicardi-Goutières syndrome, an often fatal neurological condition found in only a few families in small towns in Italy, Algeria, and Japan, and among North American Cree Indians
During DNA replication, ribonucleoside monophosphates, which are the building blocks of RNA, are inserted into DNA. During this process misinsertions can lead to lethal structural alterations. Among the study’s key findings was that Srs2 helps open the DNA structure so that Exo1 can cleave out any misplaced ribonucleoside monophosphates. Both enzymes were previously known to play a role in DNA replication and repair, but the scientists say this is the first evidence of their role in preventing and correcting mutations derived from ribonucleoside monophosphates.
The research team also found that the Srs2-Exo1cell-repair mechanism prevents mutations from accelerating in yeast already deficient in the enzyme RNaseH2. That enzyme serves as the primary removal mechanism for ribonucleoside monophosphate during cell growth. Yeast deficient in both RNaseH2 and Srs2, had a 10-fold increase in the number of mutations, chromosome losses, and chromosome breakages. These results could help scientists better understand Aicardi-Goutières syndrome, which stems from inactivation of the human RNaseH2 enzyme complex.
Citation: Potenski CJ, Niu H, Sung P, Klein HL. 2014. Avoidance of ribonucleotide-induced mutations by RNase H2 and Srs2-Exo1 mechanisms. Nature 511(7508):251-254.