Control of Mus81 nuclease during the cell cycle

Pfander, Boris; Matos, Joao

doi:10.1002/1873-3468.12727

Cited by 28 publications

(29 citation statements)

References 72 publications

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“…It is still poorly defined whether each of the two MUS81/EMEs complexes shows any cell-cycle specificity ( 4 , 18 , 20 , 35 ). Hence, we analysed if modification by CK2 was cell cycle-dependent.…”

Section: Resultsmentioning

confidence: 99%

Phosphorylation by CK2 regulates MUS81/EME1 in mitosis and after replication stress

Palma

Pugliese

Murfuni

et al. 2018

Nucleic Acids Research

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The MUS81 complex is crucial for preserving genome stability through the resolution of branched DNA intermediates in mitosis. However, untimely activation of the MUS81 complex in S-phase is dangerous. Little is known about the regulation of the human MUS81 complex and how deregulated activation affects chromosome integrity. Here, we show that the CK2 kinase phosphorylates MUS81 at Serine 87 in late-G2/mitosis, and upon mild replication stress. Phosphorylated MUS81 interacts with SLX4, and this association promotes the function of the MUS81 complex. In line with a role in mitosis, phosphorylation at Serine 87 is suppressed in S-phase and is mainly detected in the MUS81 molecules associated with EME1. Loss of CK2-dependent MUS81 phosphorylation contributes modestly to chromosome integrity, however, expression of the phosphomimic form induces DSBs accumulation in S-phase, because of unscheduled targeting of HJ-like DNA intermediates, and generates a wide chromosome instability phenotype. Collectively, our findings describe a novel regulatory mechanism controlling the MUS81 complex function in human cells. Furthermore, they indicate that, genome stability depends mainly on the ability of cells to counteract targeting of branched intermediates by the MUS81/EME1 complex in S-phase, rather than on a correct MUS81 function in mitosis.

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Section: Resultsmentioning

confidence: 99%

Phosphorylation by CK2 regulates MUS81/EME1 in mitosis and after replication stress

Palma

Pugliese

Murfuni

et al. 2018

Nucleic Acids Research

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show abstract

“…In summary, this may suggest that CDK2 might not regulate CO designation but might be involved in maturation of designated sites. Interestingly, the budding yeast counterparts of both EME1 (CO junction endonuclease MMS4 [mms4]) and BTBD12 (Slx4) have previously been shown to be targets of CDK-associated activity [ 100 – 102 ]. The implications of whether these resolvases might also be regulated by CDK activity during mammalian meiosis are still poorly understood.…”

Section: Discussionmentioning

confidence: 99%

A novel function for CDK2 activity at meiotic crossover sites

et al. 2020

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Genetic diversity in offspring is induced by meiotic recombination, which is initiated between homologs at >200 sites originating from meiotic double-strand breaks (DSBs). Of this initial pool, only 1–2 DSBs per homolog pair will be designated to form meiotic crossovers (COs), where reciprocal genetic exchange occurs between parental chromosomes. Cyclin-dependent kinase 2 (CDK2) is known to localize to so-called “late recombination nodules” (LRNs) marking incipient CO sites. However, the role of CDK2 kinase activity in the process of CO formation remains uncertain. Here, we describe the phenotype of 2 Cdk2 point mutants with elevated or decreased activity, respectively. Elevated CDK2 activity was associated with increased numbers of LRN-associated proteins, including CDK2 itself and the MutL homolog 1 (MLH1) component of the MutLγ complex, but did not lead to increased numbers of COs. In contrast, reduced CDK2 activity leads to the complete absence of CO formation during meiotic prophase I. Our data suggest an important role for CDK2 in regulating MLH1 focus numbers and that the activity of this kinase is a key regulatory factor in the formation of meiotic COs.

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“…The MUS81/EME1 complex functions primarily in G2/M, while the MUS81/EME2 in S-phase (4,34). Hence, we analysed if modification by CK2 was cell cycle-dependent.…”

Section: Ck2-mediated Phosphorylation Of Mus81 At Serine 87 Is An Earmentioning

confidence: 99%

Phosphorylation by CK2 Regulates MUS81/EME1 in Mitosis and After Replication Stress

Palma

Pugliese

Murfuni

et al. 2018

Preprint

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The MUS81 complex is crucial for preserving genome stability through the resolution of branched DNA intermediates in mitosis. However, untimely activation of the MUS81 complex in S-phase is dangerous. Little is known about the regulation of the human MUS81 complex and how deregulated activation affects chromosome integrity. Here, we show that the CK2 kinase phosphorylates MUS81 at Serine 87 in late-G2/mitosis, and upon mild replication stress. Phosphorylated MUS81 interacts with SLX4, and this association promotes the function of the MUS81 complex. In line with a role in mitosis, phosphorylation at Serine 87 is suppressed in S-phase and is mainly detected in the MUS81 molecules associated with EME1. Loss of CK2-dependent MUS81 phosphorylation contributes modestly to chromosome integrity, however, expression of the phosphomimic form induces DSBs accumulation in S-phase, because of unscheduled targeting of HJ-like DNA intermediates, and generates a wide chromosome instability phenotype. Collectively, our findings describe a novel regulatory mechanism controlling the MUS81 complex function in human cells.Furthermore, they indicate that, genome stability depends mainly on the ability of cells to counteract targeting of branched intermediates by the MUS81/EME1 complex in S-phase, rather than on a correct MUS81 function in mitosis.

show abstract

Control of Mus81 nuclease during the cell cycle

Cited by 28 publications

References 72 publications

Phosphorylation by CK2 regulates MUS81/EME1 in mitosis and after replication stress

Phosphorylation by CK2 regulates MUS81/EME1 in mitosis and after replication stress

A novel function for CDK2 activity at meiotic crossover sites

Phosphorylation by CK2 Regulates MUS81/EME1 in Mitosis and After Replication Stress

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