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Replication fork collapse and genome instability in dCMP deaminase mutant
Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA .
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA .
Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA .
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2012 (English)In: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 32, no 21, 4445-4454 p.Article in journal (Refereed) Published
Abstract [en]

Ribonucleotide reductase (RNR) and deoxycytidylate deaminase (dCMP deaminase) are pivotal allosteric enzymes required to maintain adequate pools of deoxyribonucleoside triphosphates (dNTPs) for DNA synthesis and repair. Whereas RNR inhibition slows DNA replication and activates checkpoint responses, the effect of dCMP deaminase deficiency is largely unknown. Here, we report that deleting the Schizosaccharomyces pombe dcd1(+) dCMP deaminase gene (SPBC2G2.13c) increases dCTP ∼30-fold and decreases dTTP ∼4-fold. In contrast to the robust growth of a Saccharomyces cerevisiae dcd1Δ mutant, fission yeast dcd1Δ cells delay cell cycle progression in early S phase and are sensitive to multiple DNA damaging agents, indicating impaired DNA replication and repair. DNA content profiling of dcd1Δcells differs from an RNR-deficient mutant. Dcd1 deficiency activates genome integrity checkpoints enforced by Rad3 (ATR), Cds1 (Chk2) and Chk1, and creates critical requirements for proteins involved in recovery from replication fork collapse, including the γH2AX-binding protein Brc1 and Mus81 Holliday junction resolvase. These effects correlate with increased nuclear foci of the single-stranded DNA binding protein RPA and the homologous recombination repair protein Rad52. Moreover, Brc1 suppresses spontaneous mutagenesis in dcd1Δ cells. We propose that replication forks stall and collapse in dcd1Δ cells, burdening DNA damage and checkpoint responses to maintain genome integrity.

Place, publisher, year, edition, pages
Washington: American Society Microbiology , 2012. Vol. 32, no 21, 4445-4454 p.
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Biochemistry and Molecular Biology
URN: urn:nbn:se:umu:diva-58611DOI: 10.1128/MCB.01062-12PubMedID: 22927644OAI: diva2:549272
Available from: 2012-09-04 Created: 2012-09-04 Last updated: 2014-06-12Bibliographically approved

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Sharma, SushmaChabes, Andrei
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