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

Palma, Anita; Pugliese, Giusj Monia; Murfuni, Ivana; Marabitti, Veronica; Malacaria, Eva; Rinalducci, Sara; Minoprio, Anna; Sanchez, Massimo; Mazzei, Filomena; Zolla, Lello; Franchitto, Annapaola; Pichierri, Pietro

doi:10.1101/278143

Cited by 5 publications

(29 citation statements)

References 48 publications

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“…Thus, the isolated MUS81-EME1 and MUS81-EME2 proteins are identical in substrate recognition and endonuclease activities, while their distinct roles in cells could arise See also Figures S4 and S5. ll Article from the cellular temporal controls, such as phosphorylation or association with other regulators (Palma et al, 2018;Princz et al, 2017;Sebesta et al, 2017;Waizenegger et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of the human MUS81-EME2 complex

et al. 2022

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Section: Discussionmentioning

confidence: 99%

Crystal structure of the human MUS81-EME2 complex

et al. 2022

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“…MUS81 has also been implicated in other cellular transactions, such as BIR and alternative-lengthening of telomeres (ALT) [92,99]. Apart from CDK1-mediated activation, MUS81 can also be phosphorylated by CK2 at Ser87 in G2/M and is required to maintain genome stability following RS [113]. Thus, CK2 and CDK1 phosphorylation of MUS81 in G2/M might be pre-requisite for MiDAS initiation.…”

Section: Mitotic Dna Repair Synthesis or Break-induced Mitosis Dna Synthesismentioning

confidence: 99%

“…Given the proposed important role of CDK1 for MiDAS, one cannot yet rule out that the same repair reaction might have begun prior to mitosis, namely in late G2, if normal CDK1 activity was not suppressed. Furthermore, CK2-mediated phosphorylation at Ser87 of MUS81 is also seen in late G2 cells, which may also imply that MUS81's activation could have initiated prior to mitotic onset, but further investigation is required [113].…”

Section: Mitotic Dna Repair Synthesis or Break-induced Mitosis Dna Synthesismentioning

confidence: 99%

Mind the replication gap

Mocanu

Chan

2021

R. Soc. open sci.

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Unlike bacteria, mammalian cells need to complete DNA replication before segregating their chromosomes for the maintenance of genome integrity. Thus, cells have evolved efficient pathways to restore stalled and/or collapsed replication forks during S-phase, and when necessary, also to delay cell cycle progression to ensure replication completion. However, strong evidence shows that cells can proceed to mitosis with incompletely replicated DNA when under mild replication stress (RS) conditions. Consequently, the incompletely replicated genomic gaps form, predominantly at common fragile site regions, where the converging fork-like DNA structures accumulate. These branched structures pose a severe threat to the faithful disjunction of chromosomes as they physically interlink the partially duplicated sister chromatids. In this review, we provide an overview discussing how cells respond and deal with the under-replicated DNA structures that escape from the S/G2 surveillance system. We also focus on recent research of a mitotic break-induced replication pathway (also known as mitotic DNA repair synthesis), which has been proposed to operate during prophase in an attempt to finish DNA synthesis at the under-replicated genomic regions. Finally, we discuss recent data on how mild RS may cause chromosome instability and mutations that accelerate cancer genome evolution.

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“…Abrogation of phosphorylation through expression of an unphosphorylable S87A-MUS81 allele impairs only mitotic resolution of DNA intermediates, making this form of MUS81 a separation-offunction mutant (24).…”

Section: Introductionmentioning

confidence: 99%

“…We recently reported that CK2-dependent phosphorylation of MUS81 at S87 stimulates association with SLX4 in late G2/M and regulates the function of the MUS81/EME1 complex in mitosis (24). Abrogation of phosphorylation through expression of an unphosphorylable S87A-MUS81 allele impairs only mitotic resolution of DNA intermediates, making this form of MUS81 a separation-of-function mutant (24).…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation Status Of MUS81 Is A Modifier Of Olaparib Sensitivity In BRCA2-Deficient Cells

Blandino

Malacaria

Figlioli³

et al. 2022

Preprint

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The MUS81 complex is crucial for preserving genome stability through resolution of branched DNA intermediates in mitosis and also participates in the processing of deprotected replication forks in BRCA2-deficient cells. Because of the existence of two different MUS81 complexes in mammalian cells that act in M or S-phase, whether and how the PARPi sensitivity of BRCA2-deficient cells is affected by loss of MUS81 function is unclear. Here, using a separation-of-function mutant of MUS81, we show that viability of BRCA2-deficient cells but not their PARPi sensitivity requires a fully-functional MUS81 complex in mitosis. In contrast, expression of an aberrantly active MUS81 is sufficient to confer PARPi resistance. From a mechanistic point of view, our data indicates that deregulated action of the mitotic active form of MUS81 leads to introduction of DSBs upstream reversal of stalled replication forks bypassing fork deprotection and the engagement of the S-phase MUS81 complex. Collectively, our findings describe a novel mechanism leading to PARPi resistance that involves unscheduled MUS81-dependent cleavage of intact, unreversed replication forks. Since this cleavage occurs mimicking the phosphorylated status of S87 of MUS81, our data suggest that hyperphosphorylation of this residue in S-phase might represent a novel biomarker to identify resistance to PARPi.

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

Cited by 5 publications

References 48 publications

Crystal structure of the human MUS81-EME2 complex

Crystal structure of the human MUS81-EME2 complex

Mind the replication gap

Phosphorylation Status Of MUS81 Is A Modifier Of Olaparib Sensitivity In BRCA2-Deficient Cells

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