MUS81 promotes common fragile site expression

Ying, Songmin; Minocherhomji, Sheroy; Chan, Kok-Lung; Pálmai-Pallag, Timea; Chu, Wai Kit; Wass, Theresa; Mankouri, Hocine W; Liu, Ying; Hickson, Ian D.

doi:10.1038/ncb2773

Cited by 242 publications

(292 citation statements)

References 31 publications

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“…MUS81 and ERCC1 are important for common fragile site breakage (or ''expression'') during G2/M phase, a process that aids faithful chromosome disjunction by severing intertwined DNA strands at sites of ongoing/incomplete replication (Naim et al 2013;Ying et al 2013). Consistent with this, MUS81-and ERCC1-depleted cells exhibit high frequencies of segregation defects and 53BP1-positive G1 nuclear bodies (NBs), in particular when subjected to exogenous replication stress.…”

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confidence: 57%

Roles of SLX1–SLX4, MUS81–EME1, and GEN1 in avoiding genome instability and mitotic catastrophe

Davies²,

2014

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The resolution of recombination intermediates containing Holliday junctions (HJs) is critical for genome maintenance and proper chromosome segregation. Three pathways for HJ processing exist in human cells and involve the following enzymes/complexes: BLM-TopoIIIa-RMI1-RMI2 (BTR complex), SLX1-SLX4-MUS81-EME1 (SLX-MUS complex), and GEN1. Cycling cells preferentially use the BTR complex for the removal of double HJs in S phase, with SLX-MUS and GEN1 acting at temporally distinct phases of the cell cycle. Cells lacking SLX-MUS and GEN1 exhibit chromosome missegregation, micronucleus formation, and elevated levels of 53BP1-positive G1 nuclear bodies, suggesting that defects in chromosome segregation lead to the transmission of extensive DNA damage to daughter cells. In addition, however, we found that the effects of SLX4, MUS81, and GEN1 depletion extend beyond mitosis, since genome instability is observed throughout all phases of the cell cycle. This is exemplified in the form of impaired replication fork movement and S-phase progression, endogenous checkpoint activation, chromosome segmentation, and multinucleation. In contrast to SLX4, SLX1, the nuclease subunit of the SLX1-SLX4 structure-selective nuclease, plays no role in the replication-related phenotypes associated with SLX4/MUS81 and GEN1 depletion. These observations demonstrate that the SLX1-SLX4 nuclease and the SLX4 scaffold play divergent roles in the maintenance of genome integrity in human cells.

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confidence: 57%

Roles of SLX1–SLX4, MUS81–EME1, and GEN1 in avoiding genome instability and mitotic catastrophe

Davies²,

2014

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“…However, simultaneous depletion of WRN and RAD51 does not suppress these DSBs, suggesting that MUS81 operates upstream of RAD51 in the processing of toxic replication intermediates (Franchitto et al, 2008;Murfuni et al, 2012;Murfuni et al, 2013). Furthermore, MUS81 also plays a role in the cleavage of RFs remaining at later (G2/M) stages of the cell cycle at common fragile sites, and its absence leads to an increase in anaphase bridges due to improper disjunction of sister chromatids (Naim et al, 2013;Ying et al, 2013;Pepe and West, 2014). Much less is known about the potential role of GEN1/Yen1 in facilitating replication of difficult to replicate regions, although both yeast and mammalian cells lacking MUS81 and GEN1/Yen1 show increased genome instability compared with the corresponding single mutants (Ho et al, 2010;Agmon et al, 2011;Wyatt et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

The Structure-Specific Endonucleases MUS81 and SEND1 Are Essential for Telomere Stability in Arabidopsis

et al. 2015

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Structure-specific endonucleases act to repair potentially toxic structures produced by recombination and DNA replication, ensuring proper segregation of the genetic material to daughter cells during mitosis and meiosis. Arabidopsis thaliana has two putative homologs of the resolvase (structure-specific endonuclease): GEN1/Yen1. Knockout of resolvase genes GEN1 and SEND1, individually or together, has no detectable effect on growth, fertility, or sensitivity to DNA damage. However, combined absence of the endonucleases MUS81 and SEND1 results in severe developmental defects, spontaneous cell death, and genome instability. A similar effect is not seen in mus81 gen1 plants, which develop normally and are fertile. Absence of RAD51 does not rescue mus81 send1, pointing to roles of these proteins in DNA replication rather than DNA break repair. The enrichment of S-phase histone g-H2AX foci and a striking loss of telomeric DNA in mus81 send1 further support this interpretation. SEND1 has at most a minor role in resolution of the Holliday junction but acts as an essential backup to MUS81 for resolution of toxic replication structures to ensure genome stability and to maintain telomere integrity.

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“…On the other hand, it has recently been shown that the MUS81-EME1 nuclease is responsible for chromatid breakages observed at CFSs (Fig. 5C) (Naim et al 2013;Ying et al 2013). Taken all together, mitotic cells could manage to separate replication intermediates through two alternative mechanisms: one is MUS81-mediated DNA cleavage, resulting in CFS breakage, and the other is BLM-mediated dissolution, involving UFB formation.…”

Section: Mitotic Chromosome Dynamicsmentioning

confidence: 99%

Chromosome Dynamics during Mitosis

Hirano

2015

Cold Spring Harb Perspect Biol

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The primary goal of mitosis is to partition duplicated chromosomes into daughter cells. Eukaryotic chromosomes are equipped with two distinct classes of intrinsic machineries, cohesin and condensins, that ensure their faithful segregation during mitosis. Cohesin holds sister chromatids together immediately after their synthesis during S phase until the establishment of bipolar attachments to the mitotic spindle in metaphase. Condensins, on the other hand, attempt to "resolve" sister chromatids by counteracting cohesin. The products of the balancing acts of cohesin and condensins are metaphase chromosomes, in which two rod-shaped chromatids are connected primarily at the centromere. In anaphase, this connection is released by the action of separase that proteolytically cleaves the remaining population of cohesin. Recent studies uncover how this series of events might be mechanistically coupled with each other and intricately regulated by a number of regulatory factors.

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MUS81 promotes common fragile site expression

Cited by 242 publications

References 31 publications

Roles of SLX1–SLX4, MUS81–EME1, and GEN1 in avoiding genome instability and mitotic catastrophe

Roles of SLX1–SLX4, MUS81–EME1, and GEN1 in avoiding genome instability and mitotic catastrophe

The Structure-Specific Endonucleases MUS81 and SEND1 Are Essential for Telomere Stability in Arabidopsis

Chromosome Dynamics during Mitosis

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