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      Genetic instability in budding and fission yeast—sources and mechanisms

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          Abstract

          Cells are constantly confronted with endogenous and exogenous factors that affect their genomes. Eons of evolution have allowed the cellular mechanisms responsible for preserving the genome to adjust for achieving contradictory objectives: to maintain the genome unchanged and to acquire mutations that allow adaptation to environmental changes. One evolutionary mechanism that has been refined for survival is genetic variation. In this review, we describe the mechanisms responsible for two biological processes: genome maintenance and mutation tolerance involved in generations of genetic variations in mitotic cells of both Saccharomyces cerevisiae and Schizosaccharomyces pombe. These processes encompass mechanisms that ensure the fidelity of replication, DNA lesion sensing and DNA damage response pathways, as well as mechanisms that ensure precision in chromosome segregation during cell division. We discuss various factors that may influence genome stability, such as cellular ploidy, the phase of the cell cycle, transcriptional activity of a particular region of DNA, the proficiency of DNA quality control systems, the metabolic stage of the cell and its respiratory potential, and finally potential exposure to endogenous or environmental stress.

          Abstract

          The stability of budding and fission yeast genomes is influenced by two contradictory factors: (1) the need to be fully functional, which is ensured through the replication fidelity pathways of nuclear and mitochondrial genomes through sensing and repairing DNA damage, through precise chromosome segregation during cell division; and (2) the need to acquire changes for adaptation to environmental challenges.

          Abstract

          Graphical Abstract Figure.

          The stability of budding and fission yeast genomes is influenced by two contradictory factors: (1) the need to be fully functional, which is ensured through the replication fidelity pathways of nuclear and mitochondrial genomes through sensing and repairing DNA damage, through precise chromosome segregation during cell division; and (2) the need to acquire changes for adaptation to environmental challenges.

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          Most cited references553

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          RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO.

          The RAD6 pathway is central to post-replicative DNA repair in eukaryotic cells; however, the machinery and its regulation remain poorly understood. Two principal elements of this pathway are the ubiquitin-conjugating enzymes RAD6 and the MMS2-UBC13 heterodimer, which are recruited to chromatin by the RING-finger proteins RAD18 and RAD5, respectively. Here we show that UBC9, a small ubiquitin-related modifier (SUMO)-conjugating enzyme, is also affiliated with this pathway and that proliferating cell nuclear antigen (PCNA) -- a DNA-polymerase sliding clamp involved in DNA synthesis and repair -- is a substrate. PCNA is mono-ubiquitinated through RAD6 and RAD18, modified by lysine-63-linked multi-ubiquitination--which additionally requires MMS2, UBC13 and RAD5--and is conjugated to SUMO by UBC9. All three modifications affect the same lysine residue of PCNA, suggesting that they label PCNA for alternative functions. We demonstrate that these modifications differentially affect resistance to DNA damage, and that damage-induced PCNA ubiquitination is elementary for DNA repair and occurs at the same conserved residue in yeast and humans.
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            PCNA, the maestro of the replication fork.

            Inheritance requires genome duplication, reproduction of chromatin and its epigenetic information, mechanisms to ensure genome integrity, and faithful transmission of the information to progeny. Proliferating cell nuclear antigen (PCNA)-a cofactor of DNA polymerases that encircles DNA-orchestrates several of these functions by recruiting crucial players to the replication fork. Remarkably, many factors that are involved in replication-linked processes interact with a particular face of PCNA and through the same interaction domain, indicating that these interactions do not occur simultaneously during replication. Switching of PCNA partners may be triggered by affinity-driven competition, phosphorylation, proteolysis, and modification of PCNA by ubiquitin and SUMO.
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              An ER-mitochondria tethering complex revealed by a synthetic biology screen.

              Communication between organelles is an important feature of all eukaryotic cells. To uncover components involved in mitochondria/endoplasmic reticulum (ER) junctions, we screened for mutants that could be complemented by a synthetic protein designed to artificially tether the two organelles. We identified the Mmm1/Mdm10/Mdm12/Mdm34 complex as a molecular tether between ER and mitochondria. The tethering complex was composed of proteins resident of both ER and mitochondria. With the use of genome-wide mapping of genetic interactions, we showed that the components of the tethering complex were functionally connected to phospholipid biosynthesis and calcium-signaling genes. In mutant cells, phospholipid biosynthesis was impaired. The tethering complex localized to discrete foci, suggesting that discrete sites of close apposition between ER and mitochondria facilitate interorganelle calcium and phospholipid exchange.
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                Author and article information

                Journal
                FEMS Microbiol Rev
                FEMS Microbiol. Rev
                femsre
                femsre
                FEMS Microbiology Reviews
                Oxford University Press
                0168-6445
                1574-6976
                24 June 2015
                November 2015
                24 June 2015
                : 39
                : 6
                : 917-967
                Affiliations
                [1 ]Laboratory of Mutagenesis and DNA Repair, Institute of Biochemistry and Biophysics, Polish Academy of Science, 02-106 Warsaw, Poland
                [2 ]Department of Genetics, Institute of Biochemistry and Biophysics, Polish Academy of Science, 02-106 Warsaw, Poland
                Author notes
                [* ] Corresponding author: Laboratory of Mutagenesis and DNA Repair, Institute of Biochemistry and Biophysics, Polish Academy of Science, 02-106 Warsaw, Poland. Tel: +4822-5921314; Fax: +4822-5922190; E-mail: ada@ 123456ibb.waw.pl
                Article
                10.1093/femsre/fuv028
                4608483
                26109598
                151b1800-c3c4-487a-ab62-0c307fada070
                © FEMS 2015.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@ 123456oup.com

                History
                : 26 May 2015
                : 14 December 2014
                Page count
                Pages: 51
                Categories
                Review Article
                Custom metadata
                November 2015

                Microbiology & Virology
                fidelity of replication,dntp pool,homologous recombination,transcription-associated genome instability,aneuploidy,mitochondrial genome maintenance

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