Role of Inner Nuclear Membrane Protein Complex Lem2-Nur1 in Heterochromatic Gene Silencing

Banday, Shahid; Farooq, Zeenat; Rashid, Romana; Abdullah, Ehsaan; Altaf, Mohammad

doi:10.1074/jbc.m116.743211

Cited by 39 publications

(63 citation statements)

References 48 publications

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“…It is known that Lem2 binds to chromatin through its conserved LEM domain (Gonzalez et al., ) and that the S. pombe Lem2 also affects chromatin functions (Banday, Farooq, Rashid, Abdullah, & Altaf, ; Barrales et al., ; Gonzalez et al., ; Tange et al., ). Thus, we investigated the DNA‐binding ability of Lem2 using an on‐bead DNA‐binding assay (Figure ).…”

Section: Resultsmentioning

confidence: 99%

“…Lem2 is associated with chromatin functions, such as the maintenance of the centromeres and the telomeres (Banday et al., ; Barrales et al., ), genome stability and long‐terminal repeat recombination (Tange et al., ), as well as checkpoint signaling (Hayles et al., ; Xu, ). These Lem2 functions, at least in part, are distinct from those of Man1, as man1Δ mutants show phenotypes that are distinct from those of lem2Δ mutants (Barrales et al., ; Gonzalez et al., ; Tange et al., ).…”

Section: Discussionmentioning

confidence: 99%

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Lem2 is retained at the nuclear envelope through its interaction with Bqt4 in fission yeast

et al. 2018

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Inner nuclear membrane (INM) proteins are thought to play important roles in modulating nuclear organization and function through their interactions with chromatin. However, these INM proteins share redundant functions in metazoans that pose difficulties for functional studies. The fission yeast Schizosaccharomyces pombe exhibits a relatively small number of INM proteins, and molecular genetic tools are available to separate their redundant functions. In S. pombe, it has been reported that among potentially redundant INM proteins, Lem2 displays a unique genetic interaction with another INM protein, Bqt4, which is involved in anchoring telomeres to the nuclear envelope. Double mutations in the lem2 and bqt4 genes confer synthetic lethality during vegetative growth. Here, we show that Lem2 is retained at the nuclear envelope through its interaction with Bqt4, as the loss of Bqt4 results in the exclusive accumulation of Lem2 to the spindle pole body (SPB). An N‐terminal nucleoplasmic region of Lem2 bears affinity to both Bqt4 and the SPB in a competitive manner. In contrast, the synthetic lethality of the lem2 bqt4 double mutant is suppressed by the C‐terminal region of Lem2. These results indicate that the N‐terminal and C‐terminal domains of Lem2 show independent functions with respect to Bqt4.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Lem2 is retained at the nuclear envelope through its interaction with Bqt4 in fission yeast

et al. 2018

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“…This conserved pathway may likewise underlie the requirement for Src1, a LEM-domain protein in A. nidulans, in the formation of stable nuclei (39). This body of work suggests that LEM2 plays a specific, initiating role in 14 coordinating membrane remodeling events, particularly during nuclear assembly, in addition to the other roles it plays as a nuclear envelope resident during interphase (31,35,(40)(41)(42)(43)(44)(45).…”

Section: Discussionmentioning

confidence: 99%

LEM2 recruits CHMP7 for ESCRT-mediated nuclear envelope closure in fission yeast and human cells

LaJoie

Chen

et al. 2016

Preprint

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ESCRT-III proteins have been implicated in sealing the nuclear envelope in mammals, spindle pole body dynamics in fission yeast, and surveillance of defective nuclear pore complexes in budding yeast. Here, we report that Lem2p (LEM2), a member of the LEM (Lap2-Emerin-Man1) family of inner nuclear membrane proteins, and the ESCRT-II/ESCRT-III hybrid protein Cmp7p (CHMP7), work together to recruit additional ESCRT-III proteins to holes in the nuclear membrane. In S. pombe, deletion of the ATPase vps4 leads to severe defects in nuclear morphology and integrity. These phenotypes are suppressed by loss-of-function mutations that arise spontaneously in lem2 or cmp7, implying that these proteins may function upstream in the same pathway. Building on these genetic interactions, we explored the role of LEM2 during nuclear envelope reformation in human cells. We found that CHMP7 and LEM2 enrich at the same region of the chromatin disc periphery during this window of cell division, and that CHMP7 can bind directly to the C-terminal domain of LEM2 in vitro. We further found that, during nuclear envelope formation, recruitment of the ESCRT factors CHMP7, CHMP2A and IST1/CHMP8 all depend on LEM2 in human cells. We conclude that Lem2p/LEM2 is a conserved nuclear sitespecific adaptor that recruits Cmp7p/CHMP7 and downstream ESCRT factors to the nuclear envelope.. CC-BY-NC-ND 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/049312 doi: bioRxiv preprint first posted online Apr. 19, 2016; 3 SignificanceThe molecular mechanism for sealing newly formed nuclear envelopes was unclear until the recent discovery that ESCRT-III proteins mediate this process. CHMP7, in particular, was identified as an early-acting factor that recruits other ESCRT-III proteins to the nuclear envelope.A fundamental aspect of the varied roles of ESCRT factors is their recruitment by site-specific adaptors, yet the central question of how the ESCRT machinery is targeted to nuclear membranes has remained outstanding. Our study identifies the inner nuclear membrane protein LEM2 as a key, conserved factor that recruits CHMP7 and downstream ESCRT-III proteins to breaches in the nuclear envelope.

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“…Lem2 orthologues function in complex with another INM protein Nur1 to promote heterochromatin tethering and heterochromatic gene silencing 13–15 . In S. japonicus , Nur1 largely co-localized with Lem2 throughout the cell cycle, enriching at the NE ‘tails’ at the end of mitosis (Fig.…”

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confidence: 99%

“…Since the Lem2-Nur1 complex is involved in heterochromatin maintenance and its tethering to the NE 13,14,34,35 , we analysed if the Nur1-Lem2 clusters in ESCRT-III-deficient cells co-localized with heterochromatin. In fission yeast, all heterochromatin including sub-telomeric and peri-centromeric sequences localises to the nuclear periphery during interphase 36 .…”

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ESCRT-III/Vps4 controls heterochromatin-nuclear envelope attachments

Pieper

Sprenger

Teis

et al. 2019

Preprint

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23In eukaryotes chromosomes are compartmentalized within the nucleus 24 delimited by the double membrane of the nuclear envelope (NE). Defects in the 25 function and structure of the NE are linked to disease 1,2 . During interphase, the 26 NE organizes the genome and regulates its expression 3 . As cells enter mitosis, 27 chromosomes are released from the NE, which is then remodelled to form the 28 daughter nuclei at mitotic exit 4 . Interactions between the NE and chromatin 29 underpinning both interphase and post-mitotic NE functions are executed by 30 inner nuclear membrane (INM) proteins such as members of the evolutionarily 31 conserved chromatin-binding LEM-domain family 5-8 . How chromatin tethering 32 by these transmembrane proteins is controlled in interphase and if such a 33 regulation contributes to subsequent NE dynamics in mitosis remains unclear. 34 Here we probe these fundamental questions using an emerging model 35 organism, the fission yeast Schizosaccharomyces japonicus, which breaks 36 and reforms the NE during mitosis 9,10 . We show that attachments between 37 heterochromatin and the transmembrane Lem2-Nur1 complex are 38 continuously remodelled in interphase by the ESCRT-III/AAA-ATPase Vps4 39 machinery. ESCRT-III/Vps4 mediates the release of Lem2-Nur1 from 40 heterochromatin as a prerequisite for the timely progression through mitosis. 41 Failure in this process leads to persistent association of chromosomes with 42 the INM, which prevents Lem2-Nur1 from re-localizing to the sites of NE 43 sealing around the mitotic spindle and severely delays re-establishment of 44 nucleocytoplasmic compartmentalization. Our work establishes the INM 45 transmembrane Lem2-Nur1 complex as a 'substrate' for ESCRT-III/Vps4 to 46 couple dynamic tethering of chromosomes to the INM with the establishment 47(SPB) localization 10 (Fig. 1a). Other NE proteins such as components of the nuclear 57 pore complexes (NPCs) and the second fission yeast LEM-domain protein Man1 are 58 largely excluded from the 'tails' due to their interactions with segregating 59 chromosomes at this stage of mitosis 10-12 . Thus, the 'tail' is a specialized membrane 60 domain, spatially segregated and partitioned away from the rest of the NE during 61 mitotic exit (Fig. 1a, right panel). 62 63 Lem2 orthologues function in complex with another INM protein Nur1 to promote 64 heterochromatin tethering and heterochromatic gene silencing [13][14][15] . In S. japonicus, 65Nur1 largely co-localized with Lem2 throughout the cell cycle, enriching at the NE 66 'tails' at the end of mitosis (Fig. 1b). This localization of Nur1 required Lem2, as Nur1 67 redistributed throughout the ER in lem2∆ cells (Fig. 1c). Conversely, in cells lacking 68 Nur1, less Lem2 signal was detected at the SPBs and the NE (Fig. 1d). Additionally, 69Lem2 residence time at the 'tails' was drastically reduced in Nur1-defcient cells (Fig. 70 1e). Thus, Lem2 and Nur1 appear to co-depend on each other for proper localization 71 to the NE and the SPB throughout the cell cycle. 72 73...

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Role of Inner Nuclear Membrane Protein Complex Lem2-Nur1 in Heterochromatic Gene Silencing

Cited by 39 publications

References 48 publications

Lem2 is retained at the nuclear envelope through its interaction with Bqt4 in fission yeast

Lem2 is retained at the nuclear envelope through its interaction with Bqt4 in fission yeast

LEM2 recruits CHMP7 for ESCRT-mediated nuclear envelope closure in fission yeast and human cells

ESCRT-III/Vps4 controls heterochromatin-nuclear envelope attachments

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