The yeast protein Set1p, inactivation of which alleviates telomeric position effect (TPE), contains a conserved SET domain present in chromosomal proteins involved in epigenetic control of transcription. Mec3p is required for efficient DNA-damage-dependent checkpoints at G1/S, intra-S and G2/M (refs 3-7). We show here that the SET domain of Set1p interacts with Mec3p. Deletion of SET1 increases the viability of mec3delta mutants after DNA damage (in a process that is mostly independent of Rad53p kinase, which has a central role in checkpoint control) but does not significantly affect cell-cycle progression. Deletion of MEC3 enhances TPE and attenuates the Set1delta-induced silencing defect. Furthermore, restoration of TPE in a Set1delta mutant by overexpression of the isolated SET domain requires Mec3p. Finally, deletion of MEC3 results in telomere elongation, whereas cells with deletions of both SET1 and MEC3 do not have elongated telomeres. Our findings indicate that interactions between SET1 and MEC3 have a role in DNA repair and telomere function.