We previously have reported that Saccharomyces cerevisiae mutants expressing Kllsm4Delta1, a truncated form of the KlLSM4 gene, as well as mutants in genes of the mRNA-decapping pathway, show phenotypic markers of apoptosis, increased temperature sensitivity and reduced growth in the presence of different drugs and oxidative stressing agents, such as acetic acid and H(2)O(2). To isolate multicopy extra-genic suppressors of these defects, we transformed the Kllsm4Delta1 mutant with a yeast DNA library and we selected a series of clones showing resistance to acetic acid. One of these clones carried a DNA fragment containing the HIR1 gene that encodes a transcriptional co-repressor of histone genes. The over-expression of HIR1 in the Kllsm4Delta1 mutant prevented rapid cell death during chronological aging, reduced nuclei fragmentation and increased resistance to H(2)O(2). Transcription analysis revealed that the expression of histone genes was lowered in the mutant over-expressing HIR1, indicating a relationship between the latter gene and apoptosis.