DNA Breaks Promote Genomic Instability by Impeding Proper Chromosome Segregation

Kaye, Julia; Melo, Justine A.; Cheung, Stephanie; Vaze, Moreshwar B.; Haber, James E.; Toczyski, David P.

doi:10.1016/j.cub.2004.10.051

Cited by 153 publications

(171 citation statements)

References 45 publications

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“…Despite constitutive Rad53 activation, dia2D cells exhibit highly elevated chromosome loss and GCR rates. Unrepaired replication-induced DSBs not only can cause catastrophic genome rearrangements (Chen and Kolodner 1999;Myung et al 2001;Kolodner et al 2002) but also can directly lead to failures in chromosome segregation (Kaye et al 2004). Multiple aberrations in chromosome replication and segregation pathways thus appear to underlie the high rate of genome instability of the dia2D mutant.…”

Section: Discussionmentioning

confidence: 99%

“…Dia2 thus plays a significant role in ensuring the fidelity of chromosome transmission, likely through suppression of replication-induced DSBs, which can lead directly to aneuploidy through missegregation events (Kaye et al 2004).…”

Section: -The F-box Protein Dia2 Forms An Scf Complex and Is Requiredmentioning

confidence: 99%

“…Dia2 suppresses GCRs: DNA double strand breaks can lead to whole or partial chromosome loss (Kaye et al 2004). We therefore tested whether dia2D cells are prone to genomic alterations by using a mutator assay that measures the incidence of GCRs (Chen and Kolodner 1999).…”

Section: -The F-box Protein Dia2 Forms An Scf Complex and Is Requiredmentioning

confidence: 99%

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The F-Box Protein Dia2 Overcomes Replication Impedance to Promote Genome Stability in Saccharomyces cerevisiae

et al. 2006

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The maintenance of DNA replication fork stability under conditions of DNA damage and at natural replication pause sites is essential for genome stability. Here, we describe a novel role for the F-box protein Dia2 in promoting genome stability in the budding yeast Saccharomyces cerevisiae. Like most other F-box proteins, Dia2 forms a Skp1-Cdc53/Cullin-F-box (SCF) E3 ubiquitin-ligase complex. Systematic analysis of genetic interactions between dia2D and 4400 viable gene deletion mutants revealed synthetic lethal/ synthetic sick interactions with a broad spectrum of DNA replication, recombination, checkpoint, and chromatin-remodeling pathways. dia2D strains exhibit constitutive activation of the checkpoint kinase Rad53 and elevated counts of endogenous DNA repair foci and are unable to overcome MMS-induced replicative stress. Notably, dia2D strains display a high rate of gross chromosomal rearrangements (GCRs) that involve the rDNA locus and an increase in extrachromosomal rDNA circle (ERC) formation, consistent with an observed enrichment of Dia2 in the nucleolus. These results suggest that Dia2 is essential for stable passage of replication forks through regions of damaged DNA and natural fragile regions, particularly the replication fork barrier (RFB) of rDNA repeat loci. We propose that the SCF Dia2 ubiquitin ligase serves to modify or degrade protein substrates that would otherwise impede the replication fork in problematic regions of the genome. Collapse of replication forks results in the formation of DNA double-strand breaks (DSBs) that can then lead to illegitimate recombination and genome rearrangements, both of which are thought to be underlying causes of many human cancers (Lengauer et al. 1998). Physical impediments to replication fork progression include tightly bound non-nucleosomal protein-DNA complexes, DNA secondary structures, and regions of DNA damage, whereas inadequate dNTP pools cause forks to slow and eventually stall in a non-locus-specific manner (Branzei and Foiani 2005). Accumulated DNA damage or stalled replication forks elicit a checkpoint response that results in a delay of the cell cycle, induction of damage responsive genes, and the repair or bypass of the DNA lesion (Melo and Toczyski 2002;Branzei and Foiani 2005). The DNA damage checkpoint is activated upon detection of DNA lesions in G 1 and G 2 phase, and in S-phase the latter sometimes is referred to as the intra-S checkpoint. A second response in S-phase, referred to as the replication checkpoint, is the response to delayed DNA synthesis as caused by lowered dNTP pools upon inhibition of ribonucleotide reductase by hydroxyurea (HU). It is likely that the replication and intra-S checkpoint pathways are integrated such that the key signal is stalled or slowed replication forks, due to either dNTP shortage or collision with DNA damage. The only essential function of the S-phase checkpoint is to stabilize the fork when cells undergo replicative stress (Terceroet al. 2003) and thereby prevent the accumulation of recombinog...

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Section: Discussionmentioning

confidence: 99%

Section: -The F-box Protein Dia2 Forms An Scf Complex and Is Requiredmentioning

confidence: 99%

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The F-Box Protein Dia2 Overcomes Replication Impedance to Promote Genome Stability in Saccharomyces cerevisiae

et al. 2006

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“…Cells with nuclear fragments located between two larger nuclear bodies were scored as containing ''lagging chromosomes'' (43). This phenotype has been observed after endonucleaseinduced double-strand breaks and may reflect failed separation of synapsed sister chromatids or the presence of broken acentric chromosomes (44). Cells with the nucleus at the extreme end of the cell were observed only after irradiation and were scored as ''tip cells.''…”

Section: Postreplication Delay Requires Dna Replication and Checkpointmentioning

confidence: 99%

UV irradiation induces a postreplication DNA damage checkpoint

Callegari

Kelly

2006

Proc. Natl. Acad. Sci. U.S.A.

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Eukaryotic cells irradiated with high doses of UV exhibit cell-cycle responses referred to as G 1͞S, intraS, and G2͞M checkpoints. After a moderate UV dose that approximates sunlight exposure and is lethal to fission yeast checkpoint mutants, we found unexpectedly that these cell-cycle responses do not occur. Instead, cells at all stages of the cell cycle carry lesions into S phase and delay cell-cycle progression for hours after the completion of bulk DNA synthesis. Both DNA replication and the checkpoint kinase, Chk1, are required to generate this cell-cycle response. UV-irradiation of ⌬chk1 cells causes chromosome damage and loss of viability only after cells have replicated irradiated DNA and entered mitosis. These data suggest that an important physiological role of the cell-cycle response to UV is to provide time for postreplication repair.cell cycle ͉ chk1 ͉ nucleotide excision repair ͉ yeast U V radiation from sunlight exposure induces DNA damage that is potentially lethal to cells and is carcinogenic to animals (1). Studies in fission and budding yeasts have demonstrated that genes that promote survival in UV light encode both DNA repair factors (2, 3) and checkpoint proteins that regulate the cell cycle in response to DNA damage (4, 5). These genes are conserved among eukaryotes, so diverse model systems may be used to address questions of molecular mechanism (6).The pyrimidine dimer is the most abundant form of DNA damage known to be induced by UV (7). This lesion is removed from duplex DNA by nucleotide excision repair (NER). When present during S phase, pyrimidine dimers cause gaps in the daughter DNA strand (8-12). The repair of these gaps is referred to as postreplication repair and involves bypass polymerases, homologous recombination, and other processes (13).Several eukaryotic cell-cycle responses have been observed after high-dose UV irradiation. Fission yeast UV-irradiated in G 2 delay the onset of mitosis, a response conserved in human cells that has been termed a G 2 ͞M DNA damage checkpoint (5, 14-16). It is posited that the UV sensitivity of fission yeast G 2 ͞M checkpoint mutants results from a failure to make time for the repair of UV-induced DNA lesions before mitosis (5). Budding yeast exhibit a G 1 ͞S checkpoint response that delays S phase entry after UV irradiation in G 1 (17). Because activation of the G 1 ͞S checkpoint requires NER genes, it has been suggested that the checkpoint monitors the presence of NER intermediates (12,(18)(19)(20). Mammalian cells exhibit a p53-dependent G 1 ͞S DNA damage checkpoint response that can eliminate damaged cells through apoptosis, delay entry into S phase, and facilitate NER (21). Like the G 1 ͞S checkpoint of yeast, the induction of p53 in G 1 requires NER and is independent of DNA replication (22). A NER-independent checkpoint is activated when UV lesions are present during S phase in Xenopus egg extracts and budding yeast NER mutants (18,23). In both model systems, UV lesions cause an arrest in S phase; however, this arrest appears to be ch...

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“…In yeast, the presence of a single irreparable DSB is not lethal: after initial checkpoint arrest, the broken chromosome can be replicated and persists for up to 10 cell divisions (Sandell and Zakian, 1993;Toczyski et al, 1997;Lee et al, 1998;Kaye et al, 2004). In checkpoint deficient strains (for example RAD9, RAD17 or MEC1 (similar to ATM/ATR)), cells do not even delay the first cycle and they continue to divide despite chromosome loss and genomic instability (Galgoczy and Toczyski, 2001).…”

Section: Checkpoint Adaptationmentioning

confidence: 99%

Breaking down cell cycle checkpoints and DNA repair during antigen receptor gene assembly

Callén

Nussenzweig

2007

Oncogene

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Double-strand breaks (DSBs) are intermediates in several physiological processes including V(D)J and class switch recombination. They are also potent substrates for chromosomal translocations that arise as by-products of antigen receptor gene assembly in lymphocytes. ATM is one among several key proteins involved in the detection, signaling and repair of DNA breaks. Despite redundancies in DSB signaling pathways, it has recently been demonstrated that ATM deficient lymphocytes can survive and proliferate several generations in vitro and in vivo despite harboring terminally deleted chromosomes produced by V(D)J recombination. In this review, we discuss how two complementary genome maintenance functions mediated by ATM prevent lymphocytes from adapting to persistent DNA damage.

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DNA Breaks Promote Genomic Instability by Impeding Proper Chromosome Segregation

Cited by 153 publications

References 45 publications

The F-Box Protein Dia2 Overcomes Replication Impedance to Promote Genome Stability in Saccharomyces cerevisiae

The F-Box Protein Dia2 Overcomes Replication Impedance to Promote Genome Stability in Saccharomyces cerevisiae

UV irradiation induces a postreplication DNA damage checkpoint

Breaking down cell cycle checkpoints and DNA repair during antigen receptor gene assembly

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