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The fission yeast FHIT homolog affects checkpoint control of proliferation and is regulated by mitochondrial electron transport.

ABSTRACT: Genetic analysis has strongly implicated human FHIT (Fragile Histidine Triad) as a tumor suppressor gene, being mutated in a large proportion of early-stage cancers. The functions of the FHIT protein have, however, remained elusive. Here, we investigated aph1+ , the fission yeast homolog of FHIT, for functions related to checkpoint control and oxidative metabolism. In sublethal concentrations of DNA damaging agents, aph1? mutants grew with a substantially shorter lag phase. In aph1? mutants carrying a hypomorphic allele of cds1 (the fission yeast homolog of Chk2), in addition, increased chromosome fragmentation and missegregation were found. We also found that under hypoxia or impaired electron transport function, the Aph1 protein level was strongly depressed. Previously, FHIT has been linked to regulation of the human 9-1-1 checkpoint complex constituted by Hus1, Rad1, and Rad9. In Schizosaccharomyces pombe, the levels of all three 9-1-1 proteins are all downregulated by hypoxia in similarity with Aph1. Moreover, deletion of the aph1+ gene reduced the Rad1 protein level, indicating a direct relationship between these two proteins. We conclude that the fission yeast FHIT homolog has a role in modulating DNA damage checkpoint function, possibly through an effect on the 9-1-1 complex, and that this effect may be critical under conditions of limiting oxidative metabolism and reoxygenation.

SUBMITTER: Sjolander JJ

PROVIDER: S-EPMC7003880 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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The fission yeast FHIT homolog affects checkpoint control of proliferation and is regulated by mitochondrial electron transport.

Sjölander Johanna J JJ Sunnerhagen Per P

Cell biology international 20191002 2

Genetic analysis has strongly implicated human FHIT (Fragile Histidine Triad) as a tumor suppressor gene, being mutated in a large proportion of early-stage cancers. The functions of the FHIT protein have, however, remained elusive. Here, we investigated aph1<sup>+</sup> , the fission yeast homolog of FHIT, for functions related to checkpoint control and oxidative metabolism. In sublethal concentrations of DNA damaging agents, aph1Δ mutants grew with a substantially shorter lag phase. In aph1Δ m ...[more]

PMID: 31538680

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Project description:BackgroundIn budding yeast, the replication checkpoint slows progress through S phase by inhibiting replication origin firing. In mammals, the replication checkpoint inhibits both origin firing and replication fork movement. To find out which strategy is employed in the fission yeast, Schizosaccharomyces pombe, we used microarrays to investigate the use of origins by wild-type and checkpoint-mutant strains in the presence of hydroxyurea (HU), which limits the pool of deoxyribonucleoside triphosphates (dNTPs) and activates the replication checkpoint. The checkpoint-mutant cells carried deletions either of rad3 (which encodes the fission yeast homologue of ATR) or cds1 (which encodes the fission yeast homologue of Chk2).ResultsOur microarray results proved to be largely consistent with those independently obtained and recently published by three other laboratories. However, we were able to reconcile differences between the previous studies regarding the extent to which fission yeast replication origins are affected by the replication checkpoint. We found (consistent with the three previous studies after appropriate interpretation) that, in surprising contrast to budding yeast, most fission yeast origins, including both early- and late-firing origins, are not significantly affected by checkpoint mutations during replication in the presence of HU. A few origins (approximately 3%) behaved like those in budding yeast: they replicated earlier in the checkpoint mutants than in wild type. These were located primarily in the heterochromatic subtelomeric regions of chromosomes 1 and 2. Indeed, the subtelomeric regions defined by the strongest checkpoint restraint correspond precisely to previously mapped subtelomeric heterochromatin. This observation implies that subtelomeric heterochromatin in fission yeast differs from heterochromatin at centromeres, in the mating type region, and in ribosomal DNA, since these regions replicated at least as efficiently in wild-type cells as in checkpoint-mutant cells.ConclusionThe fact that approximately 97% of fission yeast replication origins - both early and late - are not significantly affected by replication checkpoint mutations in HU-treated cells suggests that (i) most late-firing origins are restrained from firing in HU-treated cells by at least one checkpoint-independent mechanism, and (ii) checkpoint-dependent slowing of S phase in fission yeast when DNA is damaged may be accomplished primarily by the slowing of replication forks.

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The fission yeast FHIT homolog affects checkpoint control of proliferation and is regulated by mitochondrial electron transport.

Publications

The fission yeast FHIT homolog affects checkpoint control of proliferation and is regulated by mitochondrial electron transport.

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