Independent mechanisms recruit the cohesin loader protein NIPBL to sites of DNA damage

Bot, Christopher; Pfeiffer, Annika; Giordano, Fosco; Manjeera, Dharani E; Dantuma, Nico P.; Ström, Lena

doi:10.1242/jcs.197236

Cited by 46 publications

(40 citation statements)

References 50 publications

(78 reference statements)

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“…Molecular analyses of these cells indicated that NIPBLΔN is still able to bind chromatin and to mediate cohesin loading onto DNA despite the absence of MAU2. This notion is in line with recent findings stating that a mutant NIPBL construct that is incapable to interact with MAU2 is still able to stimulate the ATPase activity of the cohesin complex and to mediate DNA repair 37,38 . Similarly, Murayama and Uhlmann formerly reported that in vitro NIPBL alone displayed DNA binding properties indistinguishable from that of the kollerin complex and was able to mediate cohesin loading onto chromatin 2 .…”

Section: Discussionsupporting

confidence: 90%

MAU2 and NIPBL variants in Cornelia de Lange syndrome reveal MAU2-independent loading of cohesin and uncover a protective mechanism against early truncating mutations in NIPBL

Parenti

Diab

Gil

et al. 2018

Preprint

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Cornelia de Lange syndrome (CdLS) is a rare developmental disorder caused by mutations in genes related to the cohesin complex. For its association with chromatin, cohesin depends on a heterodimer formed by NIPBL and MAU2, which interact via their respective N-termini. Variants in NIPBL are the main cause of CdLS and result in NIPBL haploinsufficiency.Using CRISPR, we generated cells homozygous for an out-of-frame duplication in NIPBL.Remarkably, alternative translation initiation rescued NIPBL expression in these cells and produced an N-terminally truncated NIPBL that lacks MAU2-interaction domain, causing a dramatic reduction of MAU2 protein levels. Strikingly, this protective mechanism allows nearly normal amounts of cohesin to be loaded onto chromatin in a manner that is independent of functional NIPBL/MAU2 complexes and therefore in contrast to previous findings.We also report the first pathogenic variant in MAU2, a deletion of seven amino acids important for wrapping the N-terminus of NIPBL within MAU2. The mutation causes dramatic reduction of MAU2 heterodimerization with NIPBL, hence undermining the stability of both proteins.Our data confirm NIPBL haploinsufficiency as the major pathogenic mechanism of CdLS and give new insights into the molecular mechanisms responsible for this neurodevelopmental disorder. Our work also unveils an alternative translation-based mechanism that protects cells from out-of-frame variants of NIPBL and that may be of relevance in other genetic conditions.

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Section: Discussionsupporting

confidence: 90%

MAU2 and NIPBL variants in Cornelia de Lange syndrome reveal MAU2-independent loading of cohesin and uncover a protective mechanism against early truncating mutations in NIPBL

Parenti

Diab

Gil

et al. 2018

Preprint

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“…Other possible chromatin receptors for the cohesin loader are the human mediator complex, that is found at active promoters (Kagey et al 2010 ), the yeast kinetochore complex Ctf19 (Hinshaw et al 2017 ) and the heterochromatin protein HP1γ at sites of DNA damage (Bot et al 2017 ). Whether centromeric chromatin and heterochromatin hold distinct qualities that make them permissive for cohesin loading without assistance of chromatin remodellers, or whether chromatin remodellers are required cofactors for cohesin loading at these sites, remains to be determined.…”

Section: Requirements For Cohesin Loading Onto Chromatinmentioning

confidence: 99%

Conserved roles of chromatin remodellers in cohesin loading onto chromatin

2020

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Cohesin is a conserved, ring-shaped protein complex that topologically entraps DNA. This ability makes this member of the structural maintenance of chromosomes (SMC) complex family a central hub of chromosome dynamics regulation. Besides its essential role in sister chromatid cohesion, cohesin shapes the interphase chromatin domain architecture and plays important roles in transcriptional regulation and DNA repair. Cohesin is loaded onto chromosomes at centromeres, at the promoters of highly expressed genes, as well as at DNA replication forks and sites of DNA damage. However, the features that determine these binding sites are still incompletely understood. We recently described a role of the budding yeast RSC chromatin remodeler in cohesin loading onto chromosomes. RSC has a dual function, both as a physical chromatin receptor of the Scc2/Scc4 cohesin loader complex, as well as by providing a nucleosome-free template for cohesin loading. Here, we show that the role of RSC in sister chromatid cohesion is conserved in fission yeast. We discuss what is known about the broader conservation of the contribution of chromatin remodelers to cohesin loading onto chromatin.

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“…Of interest, NIPBL, recently found to be necessary for loop extrusion 24,25 , is recruited at laser induced damages in a manner that depends on DDR kinases 31 . We therefore assessed the consequences of pharmaceutical inhibition of the ATM kinase activity on the interaction frequency post-DSB.…”

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Loop extrusion as a mechanism for DNA Double-Strand Breaks repair foci formation

Arnould

Rocher

Clouaire

et al. 2020

Preprint

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DNA Double-Strand Breaks (DSBs) repair is essential to safeguard genome integrity.Upon DSBs, the ATM PI3K kinase rapidly triggers the establishment of megabase-sized, H2AX-decorated chromatin domains which further act as seeds for the formation of DNA Damage Response (DDR) foci 1 . How these foci are rapidly assembled in order to establish a "repair-prone" environment within the nucleus is yet unclear. Topologically Associating Domains (TADs) are a key feature of 3D genome organization that regulate transcription and replication, but little is known about their contribution to DNA repair processes 2,3 . Here we found that TADs are functional units of the DDR, instrumental for the correct establishment of H2AX/53BP1 chromatin domains in a manner that involves one-sided cohesin-mediated loop extrusion on both sides of the DSB. We propose a model whereby H2AX-containing nucleosomes are rapidly phosphorylated as they actively pass by DSB-anchored cohesin. Our work highlights the critical impact of chromosome conformation in the maintenance of genome integrity and provides the first example of a chromatin modification established by loop extrusion.DNA double-strand breaks induce the formation of DDR foci, which are microscopically visible and characterized by specific chromatin modifications (H2AX, ubiquitin accumulation, histone H1 depletion) and the accumulation of DDR factors (53BP1, MDC1) 4-6 . Previous evidence indicated that chromosome architecture may control H2AX spreading. Indeed, H2AX domain boundaries were found in some instances to coincide with TAD boundaries 7 .Moreover, super-resolution light microscopy revealed that CTCF, which demarcates TAD boundaries in undamaged cells, is juxtaposed to γH2AX foci 8 . In addition, 53BP1 can form nanodomains which frequently overlap with a TAD, as detected by DNA-FISH 9 . Highresolution ChIP-seq mapping following the induction of multiple DSB at annotated positions

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Independent mechanisms recruit the cohesin loader protein NIPBL to sites of DNA damage

Cited by 46 publications

References 50 publications

MAU2 and NIPBL variants in Cornelia de Lange syndrome reveal MAU2-independent loading of cohesin and uncover a protective mechanism against early truncating mutations in NIPBL

MAU2 and NIPBL variants in Cornelia de Lange syndrome reveal MAU2-independent loading of cohesin and uncover a protective mechanism against early truncating mutations in NIPBL

Conserved roles of chromatin remodellers in cohesin loading onto chromatin

Loop extrusion as a mechanism for DNA Double-Strand Breaks repair foci formation

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