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Journal articles on the topic 'DNA double-strand breaks, Sae2'

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Published: 9 March 2023

Last updated: 10 March 2023

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1

Yu, Tai-Yuan, Michael T. Kimble, and Lorraine S. Symington. "Sae2 antagonizes Rad9 accumulation at DNA double-strand breaks to attenuate checkpoint signaling and facilitate end resection." Proceedings of the National Academy of Sciences 115, no. 51 (December 3, 2018): E11961—E11969. http://dx.doi.org/10.1073/pnas.1816539115.

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The Mre11-Rad50-Xrs2NBS1 complex plays important roles in the DNA damage response by activating the Tel1ATM kinase and catalyzing 5′–3′ resection at DNA double-strand breaks (DSBs). To initiate resection, Mre11 endonuclease nicks the 5′ strands at DSB ends in a reaction stimulated by Sae2CtIP. Accordingly, Mre11-nuclease deficient (mre11-nd) and sae2Δ mutants are expected to exhibit similar phenotypes; however, we found several notable differences. First, sae2Δ cells exhibit greater sensitivity to genotoxins than mre11-nd cells. Second, sae2Δ is synthetic lethal with sgs1Δ, whereas the mre11-nd sgs1Δ mutant is viable. Third, Sae2 attenuates the Tel1-Rad53CHK2 checkpoint and antagonizes Rad953BP1 accumulation at DSBs independent of Mre11 nuclease. We show that Sae2 competes with other Tel1 substrates, thus reducing Rad9 binding to chromatin and to Rad53. We suggest that persistent Sae2 binding at DSBs in the mre11-nd mutant counteracts the inhibitory effects of Rad9 and Rad53 on Exo1 and Dna2-Sgs1–mediated resection, accounting for the different phenotypes conferred by mre11-nd and sae2Δ mutations. Collectively, these data show a resection initiation independent role for Sae2 at DSBs by modulating the DNA damage checkpoint.

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2

Fu, Qiong, Julia Chow, Kara A. Bernstein, Nodar Makharashvili, Sucheta Arora, Chia-Fang Lee, Maria D. Person, Rodney Rothstein, and Tanya T. Paull. "Phosphorylation-Regulated Transitions in an Oligomeric State Control the Activity of the Sae2 DNA Repair Enzyme." Molecular and Cellular Biology 34, no. 5 (December 16, 2013): 778–93. http://dx.doi.org/10.1128/mcb.00963-13.

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In the DNA damage response, many repair and signaling molecules mobilize rapidly at the sites of DNA double-strand breaks. This network of immediate responses is regulated at the level of posttranslational modifications that control the activation of DNA processing enzymes, protein kinases, and scaffold proteins to coordinate DNA repair and checkpoint signaling. Here we investigated the DNA damage-induced oligomeric transitions of the Sae2 protein, an important enzyme in the initiation of DNA double-strand break repair. Sae2 is a target of multiple phosphorylation events, which we identified and characterizedin vivoin the budding yeastSaccharomyces cerevisiae. Both cell cycle-dependent and DNA damage-dependent phosphorylation sites in Sae2 are important for the survival of DNA damage, and the cell cycle-regulated modifications are required to prime the damage-dependent events. We found that Sae2 exists in the form of inactive oligomers that are transiently released into smaller active units by this series of phosphorylations. DNA damage also triggers removal of Sae2 through autophagy and proteasomal degradation, ensuring that active Sae2 is present only transiently in cells. Overall, this analysis provides evidence for a novel type of protein regulation where the activity of an enzyme is controlled dynamically by posttranslational modifications that regulate its solubility and oligomeric state.

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3

Yu, Tai-Yuan, Valerie E. Garcia, and Lorraine S. Symington. "CDK and Mec1/Tel1-catalyzed phosphorylation of Sae2 regulate different responses to DNA damage." Nucleic Acids Research 47, no. 21 (September 25, 2019): 11238–49. http://dx.doi.org/10.1093/nar/gkz814.

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Abstract Sae2 functions in the DNA damage response by controlling Mre11-Rad50-Xrs2 (MRX)-catalyzed end resection, an essential step for homology-dependent repair of double-strand breaks (DSBs), and by attenuating DNA damage checkpoint signaling. Phosphorylation of Sae2 by cyclin-dependent kinase (CDK1/Cdc28) activates the Mre11 endonuclease, while the physiological role of Sae2 phosphorylation by Mec1 and Tel1 checkpoint kinases is not fully understood. Here, we compare the phenotype of sae2 mutants lacking the main CDK (sae2-S267A) or Mec1 and Tel1 phosphorylation sites (sae2-5A) with sae2Δ and Mre11 nuclease defective (mre11-nd) mutants. The phosphorylation-site mutations confer DNA damage sensitivity, but not to the same extent as sae2Δ. The sae2-S267A mutation is epistatic to mre11-nd for camptothecin (CPT) sensitivity and synergizes with sgs1Δ, whereas sae2-5A synergizes with mre11-nd and exhibits epistasis with sgs1Δ. We find that attenuation of checkpoint signaling by Sae2 is mostly independent of Mre11 endonuclease activation but requires Mec1 and Tel1-dependent phosphorylation of Sae2. These results support a model whereby CDK-catalyzed phosphorylation of Sae2 activates resection via Mre11 endonuclease, whereas Sae2 phosphorylation by Mec1 and Tel1 promotes resection by the Dna2-Sgs1 and Exo1 pathways indirectly by dampening the DNA damage response.

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4

Cannavo, Elda, Giordano Reginato, and Petr Cejka. "Stepwise 5′ DNA end-specific resection of DNA breaks by the Mre11-Rad50-Xrs2 and Sae2 nuclease ensemble." Proceedings of the National Academy of Sciences 116, no. 12 (February 28, 2019): 5505–13. http://dx.doi.org/10.1073/pnas.1820157116.

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To repair DNA double-strand breaks by homologous recombination, the 5′-terminated DNA strands must first be resected to produce 3′ overhangs. Mre11 fromSaccharomyces cerevisiaeis a 3′ → 5′ exonuclease that is responsible for 5′ end degradation in vivo. Using plasmid-length DNA substrates and purified recombinant proteins, we show that the combined exonuclease and endonuclease activities of recombinant MRX-Sae2 preferentially degrade the 5′-terminated DNA strand, which extends beyond the vicinity of the DNA end. Mechanistically, Rad50 restricts the Mre11 exonuclease in an ATP binding-dependent manner, preventing 3′ end degradation. Phosphorylated Sae2, along with stimulating the MRX endonuclease as shown previously, also overcomes this inhibition to promote the 3′ → 5′ exonuclease of MRX, which requires ATP hydrolysis by Rad50. Our results support a model in which MRX-Sae2 catalyzes 5′-DNA end degradation by stepwise endonucleolytic DNA incisions, followed by exonucleolytic 3′ → 5′ degradation of the individual DNA fragments. This model explains how both exonuclease and endonuclease activities of Mre11 functionally integrate within the MRX-Sae2 ensemble to resect 5′-terminated DNA.

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5

Chen, Huan, Roberto A. Donnianni, Naofumi Handa, Sarah K. Deng, Julyun Oh, Leonid A. Timashev, Stephen C. Kowalczykowski, and Lorraine S. Symington. "Sae2 promotes DNA damage resistance by removing the Mre11–Rad50–Xrs2 complex from DNA and attenuating Rad53 signaling." Proceedings of the National Academy of Sciences 112, no. 15 (March 23, 2015): E1880—E1887. http://dx.doi.org/10.1073/pnas.1503331112.

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The Mre11–Rad50–Xrs2/NBS1 (MRX/N) nuclease/ATPase complex plays structural and catalytic roles in the repair of DNA double-strand breaks (DSBs) and is the DNA damage sensor for Tel1/ATM kinase activation. Saccharomyces cerevisiae Sae2 can function with MRX to initiate 5′-3′ end resection and also plays an important role in attenuation of DNA damage signaling. Here we describe a class of mre11 alleles that suppresses the DNA damage sensitivity of sae2Δ cells by accelerating turnover of Mre11 at DNA ends, shutting off the DNA damage checkpoint and allowing cell cycle progression. The mre11 alleles do not suppress the end resection or hairpin-opening defects of the sae2Δ mutant, indicating that these functions of Sae2 are not responsible for DNA damage resistance. The purified MP110LRX complex shows reduced binding to single- and double-stranded DNA in vitro relative to wild-type MRX, consistent with the increased turnover of Mre11 from damaged sites in vivo. Furthermore, overproduction of Mre11 causes DNA damage sensitivity only in the absence of Sae2. Together, these data suggest that it is the failure to remove Mre11 from DNA ends and attenuate Rad53 kinase signaling that causes hypersensitivity of sae2Δ cells to clastogens.

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6

Nicolette, Matthew L., Kihoon Lee, Zhi Guo, Mridula Rani, Julia M. Chow, Sang Eun Lee, and Tanya T. Paull. "Mre11–Rad50–Xrs2 and Sae2 promote 5′ strand resection of DNA double-strand breaks." Nature Structural & Molecular Biology 17, no. 12 (November 21, 2010): 1478–85. http://dx.doi.org/10.1038/nsmb.1957.

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7

Rattray, Alison J., Carolyn B. McGill, Brenda K. Shafer, and Jeffrey N. Strathern. "Fidelity of Mitotic Double-Strand-Break Repair in Saccharomyces cerevisiae: A Role for SAE2/COM1." Genetics 158, no. 1 (May 1, 2001): 109–22. http://dx.doi.org/10.1093/genetics/158.1.109.

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Abstract Errors associated with the repair of DNA double-strand breaks (DSBs) include point mutations caused by misincorporation during repair DNA synthesis or novel junctions made by nonhomologous end joining (NHEJ). We previously demonstrated that DNA synthesis is ∼100-fold more error prone when associated with DSB repair. Here we describe a genetic screen for mutants that affect the fidelity of DSB repair. The substrate consists of inverted repeats of the trp1 and CAN1 genes. Recombinational repair of a site-specific DSB within the repeat yields TRP1 recombinants. Errors in the repair process can be detected by the production of canavanine-resistant (can1) mutants among the TRP1 recombinants. In wild-type cells the recombinational repair process is efficient and fairly accurate. Errors resulting in can1 mutations occur in <1% of the TRP1 recombinants and most appear to be point mutations. We isolated several mutant strains with altered fidelity of recombination. Here we characterize one of these mutants that revealed an ∼10-fold elevation in the frequency of can1 mutants among TRP1 recombinants. The gene was cloned by complementation of a coincident sporulation defect and proved to be an allele of SAE2/COM1. Physical analysis of the can1 mutants from sae2/com1 strains revealed that many were a novel class of chromosome rearrangement that could reflect break-induced replication (BIR) and NHEJ. Strains with either the mre11s-H125N or rad50s-K81I alleles had phenotypes in this assay that are similar to that of the sae2/com1Δ strain. Our data suggest that Sae2p/Com1p plays a role in ensuring that both ends of a DSB participate in a recombination event, thus avoiding BIR, possibly by regulating the nuclease activity of the Mre11p/Rad50p/Xrs2p complex.

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8

Akamatsu, Yufuko, Yasuto Murayama, Takatomi Yamada, Tomofumi Nakazaki, Yasuhiro Tsutsui, Kunihiro Ohta, and Hiroshi Iwasaki. "Molecular Characterization of the Role of the Schizosaccharomyces pombe nip1+/ctp1+ Gene in DNA Double-Strand Break Repair in Association with the Mre11-Rad50-Nbs1 Complex." Molecular and Cellular Biology 28, no. 11 (March 31, 2008): 3639–51. http://dx.doi.org/10.1128/mcb.01828-07.

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ABSTRACT The Schizosaccharomyces pombe nip1 +/ctp1 + gene was previously identified as an slr (synthetically lethal with rad2) mutant. Epistasis analysis indicated that Nip1/Ctp1 functions in Rhp51-dependent recombinational repair, together with the Rad32 (spMre11)-Rad50-Nbs1 complex, which plays important roles in the early steps of DNA double-strand break repair. Nip1/Ctp1 was phosphorylated in asynchronous, exponentially growing cells and further phosphorylated in response to bleomycin treatment. Overproduction of Nip1/Ctp1 suppressed the DNA repair defect of an nbs1-s10 mutant, which carries a mutation in the FHA phosphopeptide-binding domain of Nbs1, but not of an nbs1 null mutant. Meiotic DNA double-strand breaks accumulated in the nip1/ctp1 mutant. The DNA repair phenotypes and epistasis relationships of nip1/ctp1 are very similar to those of the Saccharomyces cerevisiae sae2/com1 mutant, suggesting that Nip1/Ctp1 is a functional homologue of Sae2/Com1, although the sequence similarity between the proteins is limited to the C-terminal region containing the RHR motif. We found that the RxxL and CxxC motifs are conserved in Schizosaccharomyces species and in vertebrate CtIP, originally identified as a cofactor of the transcriptional corepressor CtBP. However, these two motifs are not found in other fungi, including Saccharomyces and Aspergillus species. We propose that Nip1/Ctp1 is a functional counterpart of Sae2/Com1 and CtIP.

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9

Mimitou, Eleni P., and Lorraine S. Symington. "Sae2, Exo1 and Sgs1 collaborate in DNA double-strand break processing." Nature 455, no. 7214 (September 21, 2008): 770–74. http://dx.doi.org/10.1038/nature07312.

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10

Marsella, Antonio, Elisa Gobbini, Corinne Cassani, Renata Tisi, Elda Cannavo, Giordano Reginato, Petr Cejka, and Maria Pia Longhese. "Sae2 and Rif2 regulate MRX endonuclease activity at DNA double-strand breaks in opposite manners." Cell Reports 34, no. 13 (March 2021): 108906. http://dx.doi.org/10.1016/j.celrep.2021.108906.

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11

Gobbini, Elisa, Matteo Villa, Marco Gnugnoli, Luca Menin, Michela Clerici, and Maria Pia Longhese. "Sae2 Function at DNA Double-Strand Breaks Is Bypassed by Dampening Tel1 or Rad53 Activity." PLOS Genetics 11, no. 11 (November 19, 2015): e1005685. http://dx.doi.org/10.1371/journal.pgen.1005685.

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12

Baroni, Enrico, Valeria Viscardi, Hugo Cartagena-Lirola, Giovanna Lucchini, and Maria Pia Longhese. "The Functions of Budding Yeast Sae2 in the DNA Damage Response Require Mec1- and Tel1-Dependent Phosphorylation." Molecular and Cellular Biology 24, no. 10 (May 15, 2004): 4151–65. http://dx.doi.org/10.1128/mcb.24.10.4151-4165.2004.

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ABSTRACT DNA damage checkpoint pathways sense DNA lesions and transduce the signals into appropriate biological responses, including cell cycle arrest, induction of transcriptional programs, and modification or activation of repair factors. Here we show that the Saccharomyces cerevisiae Sae2 protein, known to be involved in processing meiotic and mitotic double-strand breaks, is required for proper recovery from checkpoint-mediated cell cycle arrest after DNA damage and is phosphorylated periodically during the unperturbed cell cycle and in response to DNA damage. Both cell cycle- and DNA damage-dependent Sae2 phosphorylation requires the main checkpoint kinase, Mec1, and the upstream components of its pathway, Ddc1, Rad17, Rad24, and Mec3. Another pathway, involving Tel1 and the MRX complex, is also required for full DNA damage-induced Sae2 phosphorylation, that is instead independent of the downstream checkpoint transducers Rad53 and Chk1, as well as of their mediators Rad9 and Mrc1. Mutations altering all the favored ATM/ATR phosphorylation sites of Sae2 not only abolish its in vivo phosphorylation after DNA damage but also cause hypersensitivity to methyl methanesulfonate treatment, synthetic lethality with RAD27 deletion, and decreased rates of mitotic recombination between inverted Alu repeats, suggesting that checkpoint-mediated phosphorylation of Sae2 is important to support its repair and recombination functions.

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13

Viscardi, Valeria, Enrico Baroni, Michele Romano, Giovanna Lucchini, and Maria Pia Longhese. "Sudden Telomere Lengthening Triggers a Rad53-dependent Checkpoint inSaccharomyces cerevisiae." Molecular Biology of the Cell 14, no. 8 (August 2003): 3126–43. http://dx.doi.org/10.1091/mbc.e02-11-0719.

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Telomeres are specialized functional complexes that ensure chromosome stability by protecting chromosome ends from fusions and degradation and avoiding chromosomal termini from being sensed as DNA breaks. Budding yeast Tel1 is required both for telomere metabolism and for a Rad53-dependent checkpoint responding to unprocessed double-strand breaks. We show that overexpression of a GAL1-TEL1 fusion causes transient telomere lengthening and activation of a Rad53-dependent G2/M checkpoint in cells whose telomeres are short due to the lack of either Tel1 or Yku70. Sudden telomere elongation and checkpoint-mediated cell cycle arrest are also triggered in wild-type cells by overproducing a protein fusion between the telomeric binding protein Cdc13 and the telomerase-associated protein Est1. Checkpoint activation by GAL1-TEL1 requires ongoing telomere elongation. In fact, it is turned off concomitantly with telomeres reaching a new stable length and is partially suppressed by deletion of the telomerase EST2 gene. Moreover, both telomere length rebalancing and checkpoint inactivation under galactose-induced conditions are accelerated by high levels of either the Sae2 protein, involved in double-strand breaks processing, or the negative telomere length regulator Rif2. These data suggest that sudden telomere lengthening elicits a checkpoint response that inhibits the G2/M transition.

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14

Leshets, Michael, Dharanidharan Ramamurthy, Michael Lisby, Norbert Lehming, and Ophry Pines. "Fumarase is involved in DNA double-strand break resection through a functional interaction with Sae2." Current Genetics 64, no. 3 (December 4, 2017): 697–712. http://dx.doi.org/10.1007/s00294-017-0786-4.

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15

Langerak, Petra, and Paul Russell. "Regulatory networks integrating cell cycle control with DNA damage checkpoints and double-strand break repair." Philosophical Transactions of the Royal Society B: Biological Sciences 366, no. 1584 (December 27, 2011): 3562–71. http://dx.doi.org/10.1098/rstb.2011.0070.

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Double-strand breaks (DSBs), arising from exposure to exogenous clastogens or as a by-product of endogenous cellular metabolism, pose grave threats to genome integrity. DSBs can sever whole chromosomes, leading to chromosomal instability, a hallmark of cancer. Healing broken DNA takes time, and it is therefore essential to temporarily halt cell division while DSB repair is underway. The seminal discovery of cyclin-dependent kinases as master regulators of the cell cycle unleashed a series of studies aimed at defining how the DNA damage response network delays cell division. These efforts culminated with the identification of Cdc25, the protein phosphatase that activates Cdc2/Cdk1, as a critical target of the checkpoint kinase Chk1. However, regulation works both ways, as recent studies have revealed that Cdc2 activity and cell cycle position determine whether DSBs are repaired by non-homologous end-joining or homologous recombination (HR). Central to this regulation are the proteins that initiate the processing of DNA ends for HR repair, Mre11–Rad50–Nbs1 protein complex and Ctp1/Sae2/CtIP, and the checkpoint kinases Tel1/ATM and Rad3/ATR. Here, we review recent findings and provide insight on how proteins that regulate cell cycle progression affect DSB repair, and, conversely how proteins that repair DSBs affect cell cycle progression.

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16

Wang, Weibin, James M. Daley, Youngho Kwon, Xiaoyu Xue, Danielle S. Krasner, Adam S. Miller, Kevin A. Nguyen, et al. "A DNA nick at Ku-blocked double-strand break ends serves as an entry site for exonuclease 1 (Exo1) or Sgs1–Dna2 in long-range DNA end resection." Journal of Biological Chemistry 293, no. 44 (September 17, 2018): 17061–69. http://dx.doi.org/10.1074/jbc.ra118.004769.

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The repair of DNA double-strand breaks (DSBs) by homologous recombination (HR) is initiated by nucleolytic resection of the DNA break ends. The current model, being based primarily on genetic analyses in Saccharomyces cerevisiae and companion biochemical reconstitution studies, posits that end resection proceeds in two distinct stages. Specifically, the initiation of resection is mediated by the nuclease activity of the Mre11–Rad50–Xrs2 (MRX) complex in conjunction with its cofactor Sae2, and long-range resection is carried out by exonuclease 1 (Exo1) or the Sgs1–Top3–Rmi1–Dna2 ensemble. Using fully reconstituted systems, we show here that DNA with ends occluded by the DNA end-joining factor Ku70–Ku80 becomes a suitable substrate for long-range 5′–3′ resection when a nick is introduced at a locale proximal to one of the Ku-bound DNA ends. We also show that Sgs1 can unwind duplex DNA harboring a nick, in a manner dependent on a species-specific interaction with the ssDNA-binding factor replication protein A (RPA). These biochemical systems and results will be valuable for guiding future endeavors directed at delineating the mechanistic intricacy of DNA end resection in eukaryotes.

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17

Zhu, Min, Hongchang Zhao, Oliver Limbo, and Paul Russell. "Mre11 complex links sister chromatids to promote repair of a collapsed replication fork." Proceedings of the National Academy of Sciences 115, no. 35 (August 13, 2018): 8793–98. http://dx.doi.org/10.1073/pnas.1808189115.

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Collapsed replication forks, which are a major source of DNA double-strand breaks (DSBs), are repaired by sister chromatid recombination (SCR). The Mre11–Rad50–Nbs1 (MRN) protein complex, assisted by CtIP/Sae2/Ctp1, initiates SCR by nucleolytically resecting the single-ended DSB (seDSB) at the collapsed fork. The molecular architecture of the MRN intercomplex, in which zinc hooks at the apices of long Rad50 coiled-coils connect two Mre112–Rad502 complexes, suggests that MRN also structurally assists SCR. Here, Rad50 ChIP assays in Schizosaccharomyces pombe show that MRN sequentially localizes with the seDSB and sister chromatid at a collapsed replication fork. Ctp1, which has multivalent DNA-binding and DNA-bridging activities, has the same DNA interaction pattern. Provision of an intrachromosomal repair template alleviates the nonnucleolytic requirement for MRN to repair the broken fork. Mutations of zinc-coordinating cysteines in the Rad50 hook severely impair SCR. These data suggest that the MRN complex facilitates SCR by linking the seDSB and sister chromatid.

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18

Milman, Neta, Emily Higuchi, and Gerald R. Smith. "Meiotic DNA Double-Strand Break Repair Requires Two Nucleases, MRN and Ctp1, To Produce a Single Size Class of Rec12 (Spo11)-Oligonucleotide Complexes." Molecular and Cellular Biology 29, no. 22 (September 14, 2009): 5998–6005. http://dx.doi.org/10.1128/mcb.01127-09.

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ABSTRACT Programmed DNA double-strand breaks (DSBs) in meiosis are formed by Spo11 (Rec12 in fission yeast), a topoisomerase II-like protein, which becomes covalently attached to DNA 5′ ends. For DSB repair through homologous recombination, the protein must be removed from these DNA ends. We show here that Rec12 is endonucleolytically removed from DSB ends attached to a short oligonucleotide (Rec12-oligonucleotide complex), as is Spo11 in budding yeast. Fission yeast, however, has only one size class of Rec12-oligonucleotide complexes, whereas budding yeast has two size classes, suggesting different endonucleolytic regulatory mechanisms. Rec12-oligonucleotide generation strictly requires Ctp1 (Sae2 nuclease homolog), the Rad32 (Mre11) nuclease domain, and Rad50 of the MRN complex. Surprisingly, Nbs1 is not strictly required, indicating separable roles for the MRN subunits. On the basis of these and other data, we propose that Rad32 nuclease has the catalytic site for Rec12-oligonucleotide generation and is activated by Ctp1, which plays an additional role in meiotic recombination.

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19

Öz, Robin, Sean M. Howard, Rajhans Sharma, Hanna Törnkvist, Ilaria Ceppi, Sriram KK, Erik Kristiansson, Petr Cejka, and Fredrik Westerlund. "Phosphorylated CtIP bridges DNA to promote annealing of broken ends." Proceedings of the National Academy of Sciences 117, no. 35 (August 19, 2020): 21403–12. http://dx.doi.org/10.1073/pnas.2008645117.

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The early steps of DNA double-strand break (DSB) repair in human cells involve the MRE11-RAD50-NBS1 (MRN) complex and its cofactor, phosphorylated CtIP. The roles of these proteins in nucleolytic DSB resection are well characterized, but their role in bridging the DNA ends for efficient and correct repair is much less explored. Here we study the binding of phosphorylated CtIP, which promotes the endonuclease activity of MRN, to single long (∼50 kb) DNA molecules using nanofluidic channels and compare it to the yeast homolog Sae2. CtIP bridges DNA in a manner that depends on the oligomeric state of the protein, and truncated mutants demonstrate that the bridging depends on CtIP regions distinct from those that stimulate the nuclease activity of MRN. Sae2 is a much smaller protein than CtIP, and its bridging is significantly less efficient. Our results demonstrate that the nuclease cofactor and structural functions of CtIP may depend on the same protein population, which may be crucial for CtIP functions in both homologous recombination and microhomology-mediated end-joining.

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20

Paull, Tanya T. "Making the best of the loose ends: Mre11/Rad50 complexes and Sae2 promote DNA double-strand break resection." DNA Repair 9, no. 12 (December 2010): 1283–91. http://dx.doi.org/10.1016/j.dnarep.2010.09.015.

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21

Kuo, Chen-Hsin, Yann-Lii Leu, Tong-Hong Wang, Wei-Che Tseng, Chun-Hao Feng, Shu-Huei Wang, and Chin-Chuan Chen. "A novel DNA repair inhibitor, diallyl disulfide (DADS), impairs DNA resection during DNA double-strand break repair by reducing Sae2 and Exo1 levels." DNA Repair 82 (October 2019): 102690. http://dx.doi.org/10.1016/j.dnarep.2019.102690.

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22

Godau, Julia, Lorenza P. Ferretti, Anika Trenner, Emeline Dubois, Christine von Aesch, Antoine Marmignon, Lauriane Simon, et al. "Identification of a miniature Sae2/Ctp1/CtIP ortholog from Paramecium tetraurelia required for sexual reproduction and DNA double-strand break repair." DNA Repair 77 (May 2019): 96–108. http://dx.doi.org/10.1016/j.dnarep.2019.03.011.

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23

Yu, Jianhua, Kelly Marshall, Miyuki Yamaguchi, James E. Haber, and Clifford F. Weil. "Microhomology-Dependent End Joining and Repair of Transposon-Induced DNA Hairpins by Host Factors in Saccharomyces cerevisiae." Molecular and Cellular Biology 24, no. 3 (February 1, 2004): 1351–64. http://dx.doi.org/10.1128/mcb.24.3.1351-1364.2004.

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ABSTRACT The maize, cut-and-paste transposon Ac/Ds is mobile in Saccharomyces cerevisiae, and DNA sequences of repair products provide strong genetic evidence that hairpin intermediates form in host DNA during this transposition, similar to those formed for V(D)J coding joints in vertebrates. Both DNA strands must be broken for Ac/Ds to excise, suggesting that double-strand break (DSB) repair pathways should be involved in repair of excision sites. In the absence of homologous template, as expected, Ac excisions are repaired by nonhomologous end joining (NHEJ) that can involve microhomologies close to the broken ends. However, unlike repair of endonuclease-induced DSBs, repair of Ac excisions in the presence of homologous template occurs by gene conversion only about half the time, the remainder being NHEJ events. Analysis of transposition in mutant yeast suggests roles for the Mre11/Rad50 complex, SAE2, NEJ1, and the Ku complex in repair of excision sites. Separation-of-function alleles of MRE11 suggest that its endonuclease function is more important in this repair than either its exonuclease or Rad50-binding properties. In addition, the interstrand cross-link repair gene PSO2 plays a role in end joining hairpin ends that is not seen in repair of linearized plasmids and may be involved in positioning transposase cleavage at the transposon ends.

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24

Ghodke, Indrajeet, and K. Muniyappa. "Processing of DNA Double-stranded Breaks and Intermediates of Recombination and Repair bySaccharomyces cerevisiaeMre11 and Its Stimulation by Rad50, Xrs2, and Sae2 Proteins." Journal of Biological Chemistry 288, no. 16 (February 26, 2013): 11273–86. http://dx.doi.org/10.1074/jbc.m112.439315.

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25

Casper, Anne M., Patricia W. Greenwell, Wei Tang, and Thomas D. Petes. "Chromosome Aberrations Resulting From Double-Strand DNA Breaks at a Naturally Occurring Yeast Fragile Site Composed of Inverted Ty Elements Are Independent of Mre11p and Sae2p." Genetics 183, no. 2 (July 27, 2009): 423–39. http://dx.doi.org/10.1534/genetics.109.106385.

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26

Bross, Linda, Masamichi Muramatsu, Kazuo Kinoshita, Tasuku Honjo, and Heinz Jacobs. "DNA Double-Strand Breaks." Journal of Experimental Medicine 195, no. 9 (May 6, 2002): 1187–92. http://dx.doi.org/10.1084/jem.20011749.

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The activation-induced cytidine deaminase (AID) is required for somatic hypermutation (SHM) and class-switch recombination (CSR) of immunoglobulin (Ig) genes, both of which are associated with DNA double-strand breaks (DSBs). As AID is capable of deaminating deoxy-cytidine (dC) to deoxy-uracil (dU), it might induce nicks (single strand DNA breaks) and also DNA DSBs via a U-DNA glycosylase-mediated base excision repair pathway (‘DNA-substrate model’). Alternatively, AID functions like its closest homologue Apobec1 as a catalytic subunit of a RNA editing holoenzyme (‘RNA-substrate model’). Although rearranged Vλ genes are preferred targets of SHM we found that germinal center (GC) B cells of AID-proficient and -deficient Vλ1-expressing GC B cells display a similar frequency, distribution, and sequence preference of DSBs in rearranged and also in germline Vλ1 genes. The possible roles of DSBs in relation to AID function and SHM are discussed.

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Prinz, Susanne, Angelika Amon, and Franz Klein. "Isolation of COM1, a New Gene Required to Complete Meiotic Double-Strand Break-Induced Recombination in Saccharomyces cerevisiae." Genetics 146, no. 3 (July 1, 1997): 781–95. http://dx.doi.org/10.1093/genetics/146.3.781.

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We have designed a screen to isolate mutants defective during a specific part of meiotic prophase I of the yeast Saccharomyces cerevisiae. Genes required for the repair of meiotic double-strand breaks or for the separation of recombined chromosomes are targets of this mutant hunt. The specificity is achieved by selecting for mutants that produce viable spores when recombination and reductional segregation are prevented by mutations in SPO11 and SP013 genes, but fail to yield viable spores during a normal Rec+ meiosis. We have identified and characterized a mutation com1-1, which blocks processing of meiotic double-strand breaks and which interferes with synaptonemal complex formation, homologous pairing and, as a consequence, spore viability after induction of meiotic recombination. The COM1/SAE2 gene was cloned by complementation, and the deletion mutant has a phenotype similar to com1-1. com1/sae2 mutants closely resemble the phenotype of rad50S, as assayed by phase-contrast microscopy for spore formation, physical and genetic analysis of recombination, fluorescence in situ hybridization to quantify homologous pairing and immunofluorescence and electron microscopy to determine the capability to synapse axial elements.

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Wei Zhi-Yong, Zang Li-Hui, Li Ming, Fan Wo, and Xu Yu-Jie. "Fragmentation in DNA double-strand breaks." Acta Physica Sinica 54, no. 10 (2005): 4955. http://dx.doi.org/10.7498/aps.54.4955.

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Hiom, Kevin. "Coping with DNA double strand breaks." DNA Repair 9, no. 12 (December 2010): 1256–63. http://dx.doi.org/10.1016/j.dnarep.2010.09.018.

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Phillips, John W., and William F. Morgan. "DNA double-strand breaks in mutagenesis." Environmental and Molecular Mutagenesis 22, no. 4 (1993): 214–17. http://dx.doi.org/10.1002/em.2850220406.

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Yu, Man, and Warren Masker. "T7 Single Strand DNA Binding Protein but Not T7 Helicase Is Required for DNA Double Strand Break Repair." Journal of Bacteriology 183, no. 6 (March 15, 2001): 1862–69. http://dx.doi.org/10.1128/jb.183.6.1862-1869.2001.

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ABSTRACT An in vitro system based on Escherichia coliinfected with bacteriophage T7 was used to test for involvement of host and phage recombination proteins in the repair of double strand breaks in the T7 genome. Double strand breaks were placed in a uniqueXhoI site located approximately 17% from the left end of the T7 genome. In one assay, repair of these breaks was followed by packaging DNA recovered from repair reactions and determining the yield of infective phage. In a second assay, the product of the reactions was visualized after electrophoresis to estimate the extent to which the double strand breaks had been closed. Earlier work demonstrated that in this system double strand break repair takes place via incorporation of a patch of DNA into a gap formed at the break site. In the present study, it was found that extracts prepared from uninfected E. coli were unable to repair broken T7 genomes in this in vitro system, thus implying that phage rather than host enzymes are the primary participants in the predominant repair mechanism. Extracts prepared from an E. coli recA mutant were as capable of double strand break repair as extracts from a wild-type host, arguing that the E. coli recombinase is not essential to the recombinational events required for double strand break repair. In T7 strand exchange during recombination is mediated by the combined action of the helicase encoded by gene 4 and the annealing function of the gene 2.5 single strand binding protein. Although a deficiency in the gene 2.5 protein blocked double strand break repair, a gene 4 deficiency had no effect. This argues that a strand transfer step is not required during recombinational repair of double strand breaks in T7 but that the ability of the gene 2.5 protein to facilitate annealing of complementary single strands of DNA is critical to repair of double strand breaks in T7.

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Waterman, David P., James E. Haber, and Marcus B. Smolka. "Checkpoint Responses to DNA Double-Strand Breaks." Annual Review of Biochemistry 89, no. 1 (June 20, 2020): 103–33. http://dx.doi.org/10.1146/annurev-biochem-011520-104722.

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Cells confront DNA damage in every cell cycle. Among the most deleterious types of DNA damage are DNA double-strand breaks (DSBs), which can cause cell lethality if unrepaired or cancers if improperly repaired. In response to DNA DSBs, cells activate a complex DNA damage checkpoint (DDC) response that arrests the cell cycle, reprograms gene expression, and mobilizes DNA repair factors to prevent the inheritance of unrepaired and broken chromosomes. Here we examine the DDC, induced by DNA DSBs, in the budding yeast model system and in mammals.

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Khan, Farhaan A., and Syed O. Ali. "Physiological Roles of DNA Double-Strand Breaks." Journal of Nucleic Acids 2017 (2017): 1–20. http://dx.doi.org/10.1155/2017/6439169.

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Genomic integrity is constantly threatened by sources of DNA damage, internal and external alike. Among the most cytotoxic lesions is the DNA double-strand break (DSB) which arises from the cleavage of both strands of the double helix. Cells boast a considerable set of defences to both prevent and repair these breaks and drugs which derail these processes represent an important category of anticancer therapeutics. And yet, bizarrely, cells deploy this very machinery for the intentional and calculated disruption of genomic integrity, harnessing potentially destructive DSBs in delicate genetic transactions. Under tight spatiotemporal regulation, DSBs serve as a tool for genetic modification, widely used across cellular biology to generate diverse functionalities, ranging from the fundamental upkeep of DNA replication, transcription, and the chromatin landscape to the diversification of immunity and the germline. Growing evidence points to a role of aberrant DSB physiology in human disease and an understanding of these processes may both inform the design of new therapeutic strategies and reduce off-target effects of existing drugs. Here, we review the wide-ranging roles of physiological DSBs and the emerging network of their multilateral regulation to consider how the cell is able to harness DNA breaks as a critical biochemical tool.

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Larsen, Dorthe Helena, and Manuel Stucki. "Nucleolar responses to DNA double-strand breaks." Nucleic Acids Research 44, no. 2 (November 28, 2015): 538–44. http://dx.doi.org/10.1093/nar/gkv1312.

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35

White, Ryan R., and Jan Vijg. "Do DNA Double-Strand Breaks Drive Aging?" Molecular Cell 63, no. 5 (September 2016): 729–38. http://dx.doi.org/10.1016/j.molcel.2016.08.004.

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36

Nowosielska, Anetta, and M. G. Marinus. "DNA mismatch repair-induced double-strand breaks." DNA Repair 7, no. 1 (January 2008): 48–56. http://dx.doi.org/10.1016/j.dnarep.2007.07.015.

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37

Obe, G., and M. Durante. "DNA Double Strand Breaks and Chromosomal Aberrations." Cytogenetic and Genome Research 128, no. 1-3 (2010): 8–16. http://dx.doi.org/10.1159/000303328.

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38

Jackson, S. P. "Sensing and repairing DNA double-strand breaks." Carcinogenesis 23, no. 5 (May 1, 2002): 687–96. http://dx.doi.org/10.1093/carcin/23.5.687.

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39

Redon, C. E., and W. M. Bonner. "High salt and DNA double-strand breaks." Proceedings of the National Academy of Sciences 108, no. 51 (December 12, 2011): 20281–82. http://dx.doi.org/10.1073/pnas.1117713109.

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40

Hopfner, Karl-Peter. "DNA Double-Strand Breaks Come into Focus." Cell 139, no. 1 (October 2009): 25–27. http://dx.doi.org/10.1016/j.cell.2009.09.017.

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41

Price, Brendan D., and Alan D. D’Andrea. "Chromatin Remodeling at DNA Double-Strand Breaks." Cell 152, no. 6 (March 2013): 1344–54. http://dx.doi.org/10.1016/j.cell.2013.02.011.

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Xu, Yixi, and Dongyi Xu. "Repair pathway choice for double-strand breaks." Essays in Biochemistry 64, no. 5 (July 10, 2020): 765–77. http://dx.doi.org/10.1042/ebc20200007.

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Abstract Deoxyribonucleic acid (DNA) is at a constant risk of damage from endogenous substances, environmental radiation, and chemical stressors. DNA double-strand breaks (DSBs) pose a significant threat to genomic integrity and cell survival. There are two major pathways for DSB repair: nonhomologous end-joining (NHEJ) and homologous recombination (HR). The extent of DNA end resection, which determines the length of the 3′ single-stranded DNA (ssDNA) overhang, is the primary factor that determines whether repair is carried out via NHEJ or HR. NHEJ, which does not require a 3′ ssDNA tail, occurs throughout the cell cycle. 53BP1 and the cofactors PTIP or RIF1-shieldin protect the broken DNA end, inhibit long-range end resection and thus promote NHEJ. In contrast, HR mainly occurs during the S/G2 phase and requires DNA end processing to create a 3′ tail that can invade a homologous region, ensuring faithful gene repair. BRCA1 and the cofactors CtIP, EXO1, BLM/DNA2, and the MRE11–RAD50–NBS1 (MRN) complex promote DNA end resection and thus HR. DNA resection is influenced by the cell cycle, the chromatin environment, and the complexity of the DNA end break. Herein, we summarize the key factors involved in repair pathway selection for DSBs and discuss recent related publications.

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Strumberg, Dirk, André A. Pilon, Melanie Smith, Robert Hickey, Linda Malkas, and Yves Pommier. "Conversion of Topoisomerase I Cleavage Complexes on the Leading Strand of Ribosomal DNA into 5′-Phosphorylated DNA Double-Strand Breaks by Replication Runoff." Molecular and Cellular Biology 20, no. 11 (June 1, 2000): 3977–87. http://dx.doi.org/10.1128/mcb.20.11.3977-3987.2000.

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ABSTRACT Topoisomerase I cleavage complexes can be induced by a variety of DNA damages and by the anticancer drug camptothecin. We have developed a ligation-mediated PCR (LM-PCR) assay to analyze replication-mediated DNA double-strand breaks induced by topoisomerase I cleavage complexes in human colon carcinoma HT29 cells at the nucleotide level. We found that conversion of topoisomerase I cleavage complexes into replication-mediated DNA double-strand breaks was only detectable on the leading strand for DNA synthesis, which suggests an asymmetry in the way that topoisomerase I cleavage complexes are metabolized on the two arms of a replication fork. Extension by Taq DNA polymerase was not required for ligation to the LM-PCR primer, indicating that the 3′ DNA ends are extended by DNA polymerase in vivo closely to the 5′ ends of the topoisomerase I cleavage complexes. These findings suggest that the replication-mediated DNA double-strand breaks generated at topoisomerase I cleavage sites are produced by replication runoff. We also found that the 5′ ends of these DNA double-strand breaks are phosphorylated in vivo, which suggests that a DNA 5′ kinase activity acts on the double-strand ends generated by replication runoff. The replication-mediated DNA double-strand breaks were rapidly reversible after cessation of the topoisomerase I cleavage complexes, suggesting the existence of efficient repair pathways for removal of topoisomerase I-DNA covalent adducts in ribosomal DNA.

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44

McKee, Andrew H. Z., and Nancy Kleckner. "A General Method for Identifying Recessive Diploid-Specific Mutations in Saccharomyces cerevisiae, Its Application to the Isolation of Mutants Blocked at Intermediate Stages of Meiotic Prophase and Characterization of a New Gene SAE2." Genetics 146, no. 3 (July 1, 1997): 797–816. http://dx.doi.org/10.1093/genetics/146.3.797.

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We describe a general new approach for identifying recessive mutations that affect diploid strains of yeast Saccharomyces cerevisiae and the application of this method to the identification of mutations that confer an intermediate block in meiotic prophase chromosome metabolism. The method uses a temperature-sensitive conjugation mutation ste7-1 in combination with homothallism. The mutations of interest confer a defect in spore formation that is dependent upon a gene required for initiation of meiotic recombination and development of meiosis-specific chromosome structure (SPO11). Identified in this screen were null mutations of the DMC1 gene, nonnull mutations of RAD50 (rad50S, and mutations in three new genes designated SAE1, SAE2 and SAE3 (Sporulation in the Absence of Spo Eleven). Molecular characterization of the SAE2 gene and characterization of meiotic and mitotic phenotypes of sae2 mutants are also presented. The phenotypes conferred by a sae2 null mutation are virtually indistinguishable from those conferred by the previously identified nonnull mutations of RAD50 (rad50S). Most notably, both mutations confer only weak sensitivity to the radiomimetic agent methyl methane sulfonate (MMS) but completely block resection and turnover of meiosis-specific double-strand breaks. These observations provide further evidence that this constellation of phenotypes identifies a specific molecular function.

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Chatzipapas, Konstantinos P., Panagiotis Papadimitroulas, Mohammad Obeidat, Kristen A. McConnell, Neil Kirby, George Loudos, Niko Papanikolaou, and George C. Kagadis. "Quantification of DNA double‐strand breaks using Geant4‐ DNA." Medical Physics 46, no. 1 (December 7, 2018): 405–13. http://dx.doi.org/10.1002/mp.13290.

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Slieman, Tony A., and Wayne L. Nicholson. "Artificial and Solar UV Radiation Induces Strand Breaks and Cyclobutane Pyrimidine Dimers in Bacillus subtilis Spore DNA." Applied and Environmental Microbiology 66, no. 1 (January 1, 2000): 199–205. http://dx.doi.org/10.1128/aem.66.1.199-205.2000.

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ABSTRACT The loss of stratospheric ozone and the accompanying increase in solar UV flux have led to concerns regarding decreases in global microbial productivity. Central to understanding this process is determining the types and amounts of DNA damage in microbes caused by solar UV irradiation. While UV irradiation of dormant Bacillus subtilis endospores results mainly in formation of the “spore photoproduct” 5-thyminyl-5,6-dihydrothymine, genetic evidence indicates that an additional DNA photoproduct(s) may be formed in spores exposed to solar UV-B and UV-A radiation (Y. Xue and W. L. Nicholson, Appl. Environ. Microbiol. 62:2221–2227, 1996). We examined the occurrence of double-strand breaks, single-strand breaks, cyclobutane pyrimidine dimers, and apurinic-apyrimidinic sites in spore DNA under several UV irradiation conditions by using enzymatic probes and neutral or alkaline agarose gel electrophoresis. DNA from spores irradiated with artificial 254-nm UV-C radiation accumulated single-strand breaks, double-strand breaks, and cyclobutane pyrimidine dimers, while DNA from spores exposed to artificial UV-B radiation (wavelengths, 290 to 310 nm) accumulated only cyclobutane pyrimidine dimers. DNA from spores exposed to full-spectrum sunlight (UV-B and UV-A radiation) accumulated single-strand breaks, double-strand breaks, and cyclobutane pyrimidine dimers, whereas DNA from spores exposed to sunlight from which the UV-B component had been removed with a filter (“UV-A sunlight”) accumulated only single-strand breaks and double-strand breaks. Apurinic-apyrimidinic sites were not detected in spore DNA under any of the irradiation conditions used. Our data indicate that there is a complex spectrum of UV photoproducts in DNA of bacterial spores exposed to solar UV irradiation in the environment.

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Kopa, Paulina, Anna Macieja, Grzegorz Galita, Zbigniew J. Witczak, and Tomasz Poplawski. "DNA Double Strand Breaks Repair Inhibitors: Relevance as Potential New Anticancer Therapeutics." Current Medicinal Chemistry 26, no. 8 (May 16, 2019): 1483–93. http://dx.doi.org/10.2174/0929867325666180214113154.

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DNA double-strand breaks are considered one of the most lethal forms of DNA damage. Many effective anticancer therapeutic approaches used chemical and physical methods to generate DNA double-strand breaks in the cancer cells. They include: IR and drugs which mimetic its action, topoisomerase poisons, some alkylating agents or drugs which affected DNA replication process. On the other hand, cancer cells are mostly characterized by highly effective systems of DNA damage repair. There are two main DNA repair pathways used to fix double-strand breaks: NHEJ and HRR. Their activity leads to a decreased effect of chemotherapy. Targeting directly or indirectly the DNA double-strand breaks response by inhibitors seems to be an exciting option for anticancer therapy and is a part of novel trends that arise after the clinical success of PARP inhibitors. These trends will provide great opportunities for the development of DNA repair inhibitors as new potential anticancer drugs. The main objective of this article is to address these new promising advances.

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Chadwick, K. H., and H. P. Leenhouts. "DNA Double Strand Breaks from Two Single Strand Breaks and Cell Cycle Radiation Sensitivity." Radiation Protection Dosimetry 52, no. 1-4 (April 1, 1994): 363–66. http://dx.doi.org/10.1093/oxfordjournals.rpd.a082215.

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Chadwick, K. H., and H. P. Leenhouts. "DNA Double Strand Breaks from Two Single Strand Breaks and Cell Cycle Radiation Sensitivity." Radiation Protection Dosimetry 52, no. 1-4 (April 1, 1994): 363–66. http://dx.doi.org/10.1093/rpd/52.1-4.363.

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Shanbhag, Niraj M., and Roger Greenberg. "Neighborly DISCourse: DNA double strand breaks silence transcription." Cell Cycle 9, no. 18 (September 15, 2010): 3635–36. http://dx.doi.org/10.4161/cc.9.18.13171.

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