The role of Rnr3, the minor isoform of the large subunit of the RNR complex, in DNA repair and telomere length maintenance

Telomeres are repetitive nucleotide sequences at the ends of chromosomes, which play central roles in maintaining the genome`s integrity, by distinguishing the natural chromosome ends from DNA double-strand breaks. In most human tumors and in budding yeast, telomere length is maintained by the activity of telomerase, an enzyme that adds dNTPs according to an internal RNA template.

Ribonucleotide reductase (RNR) is a universally conserved enzyme that provides the precursors for the generation of dNTPs, which are required for both DNA synthesis and repair. The catalytic activity of the major large subunit of the RNR complex, Rnr1, generates dNTPs under regular conditions. When there is DNA damage, however, an alternative large subunit, Rnr3, is upregulated, and replaces Rnr1 in RNR complexes. The reason for exchanging Rnr1 with Rnr3 is not clear.

At DSBs, telomerase activity must be inhibited in order to prevent the loss of genetic information. We previously found that Rnr1 plays a role in the sustained elongation of short telomeres by telomerase and that Rnr3 cannot replace Rnr1. This opens the possibility that Rnr3-upregulation limits telomerase activity at DSBs. We are testing this hypothesis by using artificial telomeres that contain different lengths of telomeric (TG1-3)n sequences. Our results show distinct roles for Rnr1 and Rnr3 in DSB repair and in telomere length maintenance.