Non-redundant roles in sister chromatid cohesion of the DNA helicase DDX11 and the SMC3 acetyl transferases ESCO1 and ESCO2

Faramarz, Atiq; Balk, Jesper A.; Schie, Janne J.M. van; Oostra, Anneke B.; Ghandour, Cherien A.; Rooimans, Martin A.; Wolthuis, Rob M. F.; Lange, Job de

doi:10.1371/journal.pone.0220348

Cited by 16 publications

(24 citation statements)

References 69 publications

(79 reference statements)

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“…Reduced replication fork speed was reported in HeLa cells when DDX11 knockdown was combined with the nucleotide-depleting agent hydroxyurea 40 , potentially reflecting the requirement for DDX11 to allow fork progression through difficult-to-replicate regions of DNA. In agreement with this observation, we recently reported slower fork progression upon DDX11 depletion in RPE1 cells 51 . However, in unchallenged and MMS treated chicken DT40 cells, DNA replication appeared to be independent of DDX11 52 .…”

Section: Resultssupporting

confidence: 87%

Warsaw Breakage Syndrome associated DDX11 helicase resolves G-quadruplex structures to support sister chromatid cohesion

et al. 2020

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Warsaw Breakage Syndrome (WABS) is a rare disorder related to cohesinopathies and Fanconi anemia, caused by bi-allelic mutations in DDX11. Here, we report multiple compound heterozygous WABS cases, each displaying destabilized DDX11 protein and residual DDX11 function at the cellular level. Patient-derived cell lines exhibit sensitivity to topoisomerase and PARP inhibitors, defective sister chromatid cohesion and reduced DNA replication fork speed. Deleting DDX11 in RPE1-TERT cells inhibits proliferation and survival in a TP53-dependent manner and causes chromosome breaks and cohesion defects, independent of the expressed pseudogene DDX12p. Importantly, G-quadruplex (G4) stabilizing compounds induce chromosome breaks and cohesion defects which are strongly aggravated by inactivation of DDX11 but not FANCJ. The DNA helicase domain of DDX11 is essential for sister chromatid cohesion and resistance to G4 stabilizers. We propose that DDX11 is a DNA helicase protecting against G4 induced double-stranded breaks and concomitant loss of cohesion, possibly at DNA replication forks.

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Section: Resultssupporting

confidence: 87%

Warsaw Breakage Syndrome associated DDX11 helicase resolves G-quadruplex structures to support sister chromatid cohesion

et al. 2020

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“…In humans, loss of DDX11 activity causes the cohesion syndrome Warsaw Breakage syndrome, whereas loss of ESCO2 causes Roberts syndrome. DDX11 interacts with several replication factors, such as PCNA, the 5'-flap endonuclease Flap Structure-Specific Endonuclease 1 (FEN1), the fork protection complex subunit Timeless, and CTF4, which links the activity of the Minichromosome Maintenance Protein Complex (MCM) helicase with DNA polymerases (Faramarz et al, 2020). DDX11 is believed to specialize in resolving DNA structures such as forked duplexes, 5′-flap duplexes, and antiparallel G-quadruplexes, therefore, promoting replication fork FIGURE 2 | Simplified functional interaction network of the SMC5/SMC6 complex in genome maintenance, homologous recombination, and meiosis.…”

Section: The Role Of Smc Complexes In Dna Repair: Opportunities For Ementioning

confidence: 99%

“…progression (Faramarz et al, 2020). DDX11 may promote the establishment of cohesion in three ways: (1) subtle promotion of SMC3 acetylation, (2) promotion of cohesin activity by facilitating second-strand capture, and (3) enhanced overall replication fork stability (see Figure 3).…”

Section: The Role Of Smc Complexes In Dna Repair: Opportunities For Ementioning

confidence: 99%

“…Cohesin stably prevents the sister chromatids from DNA replication until anaphase (G2 to M phases; Elbatsh et al, 2016 ). In human cells, the loader complex MAU2-NIPBL (SCC2/SCC4 in yeast) loads DNA into the cohesin complex, whereas the activity of the antagonist WINGS APART LIKE (WAPL) releases cohesin from DNA ( Faramarz et al, 2020 ) by opening an exit gate located between SMC3 and the N-terminus of the SCC1 α-kleisin ( Elbatsh et al, 2016 ; Haarhuis et al, 2017 ). Loading of cohesin by the SCC2/SCC4 loader complex involves stimulation of ATP hydrolysis by the SMC1/SMC3 ATPase domain, which is required for the stable association of cohesin with chromatin ( Elbatsh et al, 2016 ).…”

Section: Assembly Of Eukaryotic Cohesion and Structural Maintenance Omentioning

confidence: 99%

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The Role of Structural Maintenance of Chromosomes Complexes in Meiosis and Genome Maintenance: Translating Biomedical and Model Plant Research Into Crop Breeding Opportunities

Bolaños-Villegas

2021

Front. Plant Sci.

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Cohesin is a multi-unit protein complex from the structural maintenance of chromosomes (SMC) family, required for holding sister chromatids together during mitosis and meiosis. In yeast, the cohesin complex entraps sister DNAs within tripartite rings created by pairwise interactions between the central ring units SMC1 and SMC3 and subunits such as the α-kleisin SCC1 (REC8/SYN1 in meiosis). The complex is an indispensable regulator of meiotic recombination in eukaryotes. In Arabidopsis and maize, the SMC1/SMC3 heterodimer is a key determinant of meiosis. In Arabidopsis, several kleisin proteins are also essential: SYN1/REC8 is meiosis-specific and is essential for double-strand break repair, whereas AtSCC2 is a subunit of the cohesin SCC2/SCC4 loading complex that is important for synapsis and segregation. Other important meiotic subunits are the cohesin EXTRA SPINDLE POLES (AESP1) separase, the acetylase ESTABLISHMENT OF COHESION 1/CHROMOSOME TRANSMISSION FIDELITY 7 (ECO1/CTF7), the cohesion release factor WINGS APART-LIKE PROTEIN 1 (WAPL) in Arabidopsis (AtWAPL1/AtWAPL2), and the WAPL antagonist AtSWITCH1/DYAD (AtSWI1). Other important complexes are the SMC5/SMC6 complex, which is required for homologous DNA recombination during the S-phase and for proper meiotic synapsis, and the condensin complexes, featuring SMC2/SMC4 that regulate proper clustering of rDNA arrays during interphase. Meiotic recombination is the key to enrich desirable traits in commercial plant breeding. In this review, I highlight critical advances in understanding plant chromatid cohesion in the model plant Arabidopsis and crop plants and suggest how manipulation of crossover formation during meiosis, somatic DNA repair and chromosome folding may facilitate transmission of desirable alleles, tolerance to radiation, and enhanced transcription of alleles that regulate sexual development. I hope that these findings highlight opportunities for crop breeding.

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“…In support of this model, genetic fusing of ECO1 and POL30 (PCNA) restores cohesion defects otherwise present in eco1 PIP box mutants [21]. The repertoire of DNA replication factors (Chl1, Ctf4, Ctf18, MCM2-7, for example) implicated in cohesion establishment regulation has grown substantially [15,[22][23][24][25][26][27][28][29][30][31][32][33][34][35][36], highlighting the fundamental and highly conserved nature through which cohesion establishment is obligatorily coordinated with DNA replication.…”

Section: Introductionmentioning

confidence: 99%

PCNA antagonizes cohesin-dependent roles in genomic stability

Zuilkoski

Skibbens

2020

PLoS ONE

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PCNA sliding clamp binds factors through which histone deposition, chromatin remodeling, and DNA repair are coupled to DNA replication. PCNA also directly binds Eco1/Ctf7 acetyltransferase, which in turn activates cohesins and establishes cohesion between nascent sister chromatids. While increased recruitment thus explains the mechanism through which elevated levels of chromatin-bound PCNA rescue eco1 mutant cell growth, the mechanism through which PCNA instead worsens cohesin mutant cell growth remains unknown. Possibilities include that elevated levels of long-lived chromatin-bound PCNA reduce either cohesin deposition onto DNA or cohesin acetylation. Instead, our results reveal that PCNA increases the levels of both chromatin-bound cohesin and cohesin acetylation. Beyond sister chromatid cohesion, PCNA also plays a critical role in genomic stability such that high levels of chromatin-bound PCNA elevate genotoxic sensitivities and recombination rates. At a relatively modest increase of chromatin-bound PCNA, however, fork stability and progression appear normal in wildtype cells. Our results reveal that even a moderate increase of PCNA indeed sensitizes cohesin mutant cells to DNA damaging agents and in a process that involves the DNA damage response kinase Mec1(ATR), but not Tel1(ATM). These and other findings suggest that PCNA mis-regulation results in genome instabilities that normally are resolved by cohesin. Elevating levels of chromatin-bound PCNA may thus help target cohesinopathic cells linked that are linked to cancer.

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Non-redundant roles in sister chromatid cohesion of the DNA helicase DDX11 and the SMC3 acetyl transferases ESCO1 and ESCO2

Cited by 16 publications

References 69 publications

Warsaw Breakage Syndrome associated DDX11 helicase resolves G-quadruplex structures to support sister chromatid cohesion

Warsaw Breakage Syndrome associated DDX11 helicase resolves G-quadruplex structures to support sister chromatid cohesion

The Role of Structural Maintenance of Chromosomes Complexes in Meiosis and Genome Maintenance: Translating Biomedical and Model Plant Research Into Crop Breeding Opportunities

PCNA antagonizes cohesin-dependent roles in genomic stability

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