scholarly journals Mre11 complex links sister chromatids to promote repair of a collapsed replication fork

2018 ◽  
Vol 115 (35) ◽  
pp. 8793-8798 ◽  
Author(s):  
Min Zhu ◽  
Hongchang Zhao ◽  
Oliver Limbo ◽  
Paul Russell
Keyword(s):  
Sister Chromatid ◽  
Replication Fork ◽  
Dna Interaction ◽  
Coiled Coils ◽  
Molecular Architecture ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Mrn Complex ◽  
Mre11 Complex ◽  
Repair Template

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.

scholarly journals hSSB1 rapidly binds at the sites of DNA double-strand breaks and is required for the efficient recruitment of the MRN complex

2010 ◽  
Vol 39 (5) ◽  
pp. 1692-1702 ◽  
Author(s):  
Derek J. Richard ◽  
Kienan Savage ◽  
Emma Bolderson ◽  
Liza Cubeddu ◽  
Sairei So ◽  
...  
Keyword(s):  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Mrn Complex

Double-strand-break-induced homologous recombination in mammalian cells

2001 ◽  
Vol 29 (2) ◽  
pp. 196-201 ◽  
Author(s):  
R. D. Johnson ◽  
M. Jasin
Keyword(s):  
Homologous Recombination ◽  
Sister Chromatid ◽  
Mammalian Cells ◽  
Indirect Evidence ◽  
Strand Break ◽  
Double Strand Breaks ◽  
Crossing Over ◽  
Dna Double Strand Breaks ◽  
Dsb Repair ◽  
Strand Breaks

In mammalian cells, the repair of DNA double-strand breaks (DSBs) occurs by both homologous and non-homologous mechanisms. Indirect evidence, including that from gene targeting and random integration experiments, had suggested that non-homologous mechanisms were significantly more frequent than homologous ones. However, more recent experiments indicate that homologous recombination is also a prominent DSB repair pathway. These experiments show that mammalian cells use homologous sequences located at multiple positions throughout the genome to repair a DSB. However, template preference appears to be biased, with the sister chromatid being preferred by 2–3 orders of magnitude over a homologous or heterologous chromosome. The outcome of homologous recombination in mammalian cells is predominantly gene conversion that is not associated with crossing-over. The preference for the sister chromatid and the bias against crossing-over seen in mitotic mammalian cells may have developed in order to reduce the potential for genome alterations that could occur when other homologous repair templates are utilized. In attempts to understand further the mechanism of homologous recombination, the proteins that promote this process are beginning to be identified. To date, four mammalian proteins have been demonstrated conclusively to be involved in DSB repair by homologous recombination: Rad54, XRCC2, XRCC3 and BRCAI. This paper summarizes results from a number of recent studies.

Cobalt and nickel impair DNA metabolism by the oxidative stress independent pathway

Metallomics ◽  
2017 ◽  
Vol 9 (11) ◽  
pp. 1596-1609 ◽  
Author(s):  
Vineet Kumar ◽  
Rajesh Kumar Mishra ◽  
Gursharan Kaur ◽  
Dipak Dutta
Keyword(s):  
Oxidative Stress ◽  
Metal Ions ◽  
Replication Fork ◽  
Double Strand Breaks ◽  
Dna Metabolism ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Replication Fork Progression ◽  
Nickel Exposure ◽  
Cobalt And Nickel

Cobalt and nickel exposure leads to DNA double-strand breaks, decelerating replication fork progression. In parallel, the metal ions inhibit RecBCD function to block SOS-mediated repair of the damaged DNA.

scholarly journals Double-strand breaks are not the main cause of spontaneous sister chromatid exchange in wild-type yeast cells

2017 ◽  
Author(s):  
Clémence Claussin ◽  
David Porubský ◽  
Diana C.J. Spierings ◽  
Nancy Halsema ◽  
Stefan Rentas ◽  
...  
Keyword(s):  
Sister Chromatid ◽  
Sister Chromatid Exchange ◽  
Genome Instability ◽  
Single Cells ◽  
Double Strand Breaks ◽  
Yeast Cells ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Template Strand ◽  
Sister Chromatids

SummaryHomologous recombination involving sister chromatids is the most accurate, and thus most frequently used, form of recombination-mediated DNA repair. Despite its importance, sister chromatid recombination is not easily studied because it does not result in a change in DNA sequence, making recombination between sister chromatids difficult to detect. We have previously developed a novel DNA template strand sequencing technique, called Strand-seq, that can be used to map sister chromatid exchange (SCE) events genome-wide in single cells. An increase in the rate of SCE is an indicator of elevated recombination activity and of genome instability, which is a hallmark of cancer. In this study, we have adapted Strand-seq to detect SCE in the yeast Saccharomyces cerevisiae. Contrary to what is commonly thought, we find that most spontaneous SCE events are not due to the repair of DNA double-strand breaks.

scholarly journals Caenorhabditis elegans RMI2 functional homolog-2 (RMIF-2) and RMI1 (RMH-1) have both overlapping and distinct meiotic functions within the BTR complex

PLoS Genetics ◽  
2021 ◽  
Vol 17 (7) ◽  
pp. e1009663
Author(s):  
Maria Velkova ◽  
Nicola Silva ◽  
Maria Rosaria Dello Stritto ◽  
Alexander Schleiffer ◽  
Pierre Barraud ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Sister Chromatid ◽  
Meiotic Recombination ◽  
Sister Chromatid Exchange ◽  
Double Strand Breaks ◽  
Scaffolding Protein ◽  
Scaffolding Proteins ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Functional Homolog

Homologous recombination is a high-fidelity repair pathway for DNA double-strand breaks employed during both mitotic and meiotic cell divisions. Such repair can lead to genetic exchange, originating from crossover (CO) generation. In mitosis, COs are suppressed to prevent sister chromatid exchange. Here, the BTR complex, consisting of the Bloom helicase (HIM-6 in worms), topoisomerase 3 (TOP-3), and the RMI1 (RMH-1 and RMH-2) and RMI2 scaffolding proteins, is essential for dismantling joint DNA molecules to form non-crossovers (NCOs) via decatenation. In contrast, in meiosis COs are essential for accurate chromosome segregation and the BTR complex plays distinct roles in CO and NCO generation at different steps in meiotic recombination. RMI2 stabilizes the RMI1 scaffolding protein, and lack of RMI2 in mitosis leads to elevated sister chromatid exchange, as observed upon RMI1 knockdown. However, much less is known about the involvement of RMI2 in meiotic recombination. So far, RMI2 homologs have been found in vertebrates and plants, but not in lower organisms such as Drosophila, yeast, or worms. We report the identification of the Caenorhabditis elegans functional homolog of RMI2, which we named RMIF-2. The protein shows a dynamic localization pattern to recombination foci during meiotic prophase I and concentration into recombination foci is mutually dependent on other BTR complex proteins. Comparative analysis of the rmif-2 and rmh-1 phenotypes revealed numerous commonalities, including in regulating CO formation and directing COs toward chromosome arms. Surprisingly, the prevalence of heterologous recombination was several fold lower in the rmif-2 mutant, suggesting that RMIF-2 may be dispensable or less strictly required for some BTR complex-mediated activities during meiosis.

scholarly journals A Survey of Reported Disease-Related Mutations in the MRE11-RAD50-NBS1 Complex

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1678 ◽  
Author(s):  
Samiur Rahman ◽  
Marella D. Canny ◽  
Tanner A. Buschmann ◽  
Michael P. Latham
Keyword(s):  
Genomic Stability ◽  
Nijmegen Breakage Syndrome ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Response Factors ◽  
Strand Breaks ◽  
Mrn Complex ◽  
Damage Response ◽  
Biochemical Level

The MRE11-RAD50-NBS1 (MRN) protein complex is one of the primary vehicles for repairing DNA double strand breaks and maintaining the genomic stability within the cell. The role of the MRN complex to recognize and process DNA double-strand breaks as well as signal other damage response factors is critical for maintaining proper cellular function. Mutations in any one of the components of the MRN complex that effect function or expression of the repair machinery could be detrimental to the cell and may initiate and/or propagate disease. Here, we discuss, in a structural and biochemical context, mutations in each of the three MRN components that have been associated with diseases such as ataxia telangiectasia-like disorder (ATLD), Nijmegen breakage syndrome (NBS), NBS-like disorder (NBSLD) and certain types of cancers. Overall, deepening our understanding of disease-causing mutations of the MRN complex at the structural and biochemical level is foundational to the future aim of treating diseases associated with these aberrations.

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