The Emerging Role of Cohesin in the DNA Damage Response

Litwin, Ireneusz; Pilarczyk, Ewa; Wysocki, Robert

doi:10.3390/genes9120581

Cited by 68 publications

(59 citation statements)

References 220 publications

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“…Although cohesin functions to prevent premature sister chromosome segregation during mitosis, it also functions in organizing the 3D genome within interphase cells 46 , which has critical implications for DNA replication 47 , DNA repair 48 , gene transcription 49 and telomere maintenance 50 . Thus, although our primary focus was on numerical CIN resulting from PGCs (i.e.…”

Section: Discussionmentioning

confidence: 99%

Reduced Expression of Genes Regulating Cohesion Induces Chromosome Instability that May Promote Cancer and Impact Patient Outcomes

Leylek

Jeusset

Lichtensztejn

et al. 2020

Sci Rep

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chromosome instability (cin), or continual changes in chromosome complements, is an enabling feature of cancer; however, the molecular determinants of cin remain largely unknown. emerging data now suggest that aberrant sister chromatid cohesion may induce cin and contribute to cancer. to explore this possibility, we employed clinical and fundamental approaches to systematically assess the impact reduced cohesion gene expression has on cin and cancer. ten genes encoding critical functions in cohesion were evaluated and remarkably, each exhibits copy number losses in 12 common cancer types, and reduced expression is associated with worse patient survival. to gain mechanistic insight, we combined siRnA-based silencing with single cell quantitative imaging microscopy to comprehensively assess the impact reduced expression has on cin in two karyotypically stable cell lines. We show that reduced expression induces cin phenotypes, namely increases in micronucleus formation and nuclear areas. Subsequent direct tests involving a subset of prioritized genes also revealed significant changes in chromosome numbers with corresponding increases in moderate and severe cohesion defects within mitotic chromosome spreads. Collectively, our clinical and fundamental findings implicate reduced sister chromatid cohesion, resulting from gene copy number losses, as a key pathogenic event in the development and progression of many cancer types.

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Section: Discussionmentioning

confidence: 99%

Reduced Expression of Genes Regulating Cohesion Induces Chromosome Instability that May Promote Cancer and Impact Patient Outcomes

Leylek

Jeusset

Lichtensztejn

et al. 2020

Sci Rep

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“…Proteomic analysis and subsequent validation experiments showed that DCAF15 loaded into CLR4 complexes, interacted with cohesin complex members SMC1 and SMC3, and promoted their ubiquitination. We were intrigued by these interactions given the similar CRISPR screening scoring pattern of DCAF15 to the cohesin factors STAG2 and HDAC8 (Figure 2E); the shared roles of cohesin and CRL4 E3 ligases in DNA metabolism, organization, replication and repair 34, 59, 60 ; and the ability of cohesin mutations to dysregulate hematopoietic differentiation in myeloid malignancies 35 . Rather than globally controlling SMC protein levels, we speculate that CRL4-DCAF15 complexes ubiquitinate cohesin at specific genomic sites to regulate chromatin topology or repair (Figure 7G).…”

Section: Discussionmentioning

confidence: 99%

Systematic identification of cancer cell vulnerabilities to natural killer cell-mediated immune surveillance

Pech

Fong

Villalta

et al. 2019

Preprint

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12Only a subset of cancer patients respond to T-cell checkpoint inhibitors, highlighting the need for 13 alternative immunotherapeutics. We performed CRISPR-Cas9 screens in a leukemia cell line to 14 identify perturbations that enhance natural killer effector functions. Our screens defined critical 15 components of the tumor-immune synapse and highlighted the importance of cancer cell 16 interferon-g signaling in modulating NK activity. Surprisingly, disrupting the ubiquitin ligase 17 substrate adaptor DCAF15 strongly sensitized cancer cells to NK-mediated clearance. DCAF15 18 disruption induced an inflamed state in leukemic cells, including increased expression of 19 lymphocyte costimulatory molecules. Proteomic and biochemical analysis revealed that cohesin 20 complex members were endogenous client substrates of DCAF15. Genetic disruption of DCAF15 21 was phenocopied by treatment with indisulam, an anticancer drug that functions through DCAF15 22 engagement. In AML patients, reduced DCAF15 expression was associated with improved 23 survival. These findings suggest that DCAF15 inhibition may have useful immunomodulatory 24 properties in the treatment of myeloid neoplasms. 25 26 T and NK cells share effector functions, releasing cytokines and exocytosing lytic granules upon 58 activation to kill target cells. However, NK activation status is controlled by the integrated signals 59 from germline-encoded NK-activating and -inhibiting receptors (aNKRs/iNKRs). Generally, 60 iNKR ligands are expressed by normal and healthy cells, whereas aNKR ligands are upregulated 61 after DNA damage or viral insult 19,20 . MHC-I molecules provide a potent inhibitory signal sensed 62 by NK cells, enabling the innate immune system to respond productively to MHC-deficient cells. 63As a result, there is considerable interest in amplifying NK responses to cancers, as well as 64 developing NK-based cell therapies [18][19][20] . 65 66 Here, we performed genetic screens in an MHC-deficient leukemic cell line to systematically 67 identify modulators of NK-mediated anti-cancer immunity. These screens, unexpectedly, revealed 68 the potential therapeutic utility of targeting the CRL4 substrate adaptor DCAF15 in myeloid 69 malignancies. Disruption of DCAF15 strongly sensitized cancer cells to NK-mediated killing, 70 resulting from increased cancer cell expression of lymphocyte costimulatory molecules. Proteomic 71 experiments revealed that DCAF15 interacted with and promoted the ubiqitination of the cohesin 72 complex members. Treatment with indisulam, an anticancer drug that modulates DCAF15 73 function, reduced interaction with cohesin members and mimicked DCAF15 loss-of-function 74 immunophenotypes. 75 76 Results 77 78 A genome-scale CRISPR screen identifies modulators of NK effector functions 79 80We performed genome-scale CRISPR screens in K562 cells to identify perturbations that modulate 81 NK-92-mediated killing ( Figure 1A). K562 human chronic myelogenous leukemia cells are a NK-82 sensitive cancer cell line that weakly expresses MHC-...

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“…These lysine acetyltransferases have recently been shown to be important for acetylating proteins involved in the DDR and DNA repair 40 . NIPBL and cohesin are also both involved in DNA damage signalling and repair 41 and CdLS patient cells carrying NIPBL mutations display an increased DNA damage sensitivity 7 . Furthermore, we show an increase in 53BP1 foci number and size, similar to that seen in BRD4 Y430C mESCs, in NIPBL haploinsufficient LCLs.…”

Section: Discussionmentioning

confidence: 99%

Cornelia-de Lange syndrome-associated mutations cause a DNA damage signalling and repair defect

Olley

Pradeepa

FitzPatrick

et al. 2019

Preprint

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Cornelia de Lange Syndrome is a multisystem developmental disorder typically caused by mutations in 51 the gene encoding the cohesin loader NIPBL. The associated phenotype is generally assumed to be 52 the consequence of aberrant transcriptional regulation. Recently, we identified a residue substitution in 53 BRD4 associated with a Cornelia de Lange-like syndrome, that reduces BRD4 binding to acetylated 54 histones. Here we show that, although this mutation reduces BRD4-occupancy at enhancers in mouse 55 embryonic stem cells, it does not affect transcription. Rather it delays the cell cycle, increases DNA 56 damage signalling, and perturbs regulation of DNA repair in mutant cells. This uncovers a new role for 57 BRD4 in DNA repair pathway choice. Furthermore, we find evidence of a similar increase in DNA 58 damage signalling in cells derived from NIPBL-deficient individuals, suggesting that defective DNA 59 damage signalling and repair is also a feature of typical Cornelia de Lange Syndrome. 60 61 65 delayed growth 1 . CdLS is described as a 'cohesinopathy' 1 -most cases can be attributed to 66 heterozygous loss of function mutation in NIPBL encoding a protein involved in loading of the cohesin 67 complex onto chromatin 2 . Mutation in genes encoding cohesin complex proteins SMC1, SMC3 and 68 RAD21, or HDAC8 (SMC3 deacetylase), have also been identified in CdLS-like probands 2 . However 69 cells from CdLS patients have no obvious defects in sister chromatid cohesion 3 , and individuals with 70 mutations in SMC1, SMC3 and RAD21 are often considered 'atypical' in terms of facial appearance and 71 growth, and are less likely to have limb defects than those with NIPBL mutations 4 . 72Dysregulated gene expression has been proposed to be main mechanism underlying CDLS 5,6 . 73Mutations in genes encoding chromatin regulators unrelated to cohesin, such as ANKRD11, KMT2A, 74AFF4 and the bromodomain and extra-terminal domain (BET) protein BRD4, have been reported to 75 cause CdLS-like phenotypes 1 suggesting that chromatin dysregulation may play a role in CdLS as well. 76Additionally, increased sensitivity to DNA damage has been reported in CdLS patient cells 7 , but the 77 mechanism underlying this defect is unknown and its participation in the disease aetiology remains 78 unclear. 79Recently, we described de novo deletion and missense mutations in BRD4 associated with a clinical 80 phenotype overlapping CdLS 8 . BRD4 binds acetylated lysines residues in histones H3 and H4 through 81 its two N-terminal bromodomain domains (BD). BRD4 localises to promoters and enhancers of active 82 genes and is particularly enriched at super enhancers (SEs) 9,10 . BRD4 is a key regulator of transcription;; 83 through its C-terminal domain it recruits positive transcription elongation factor (P-TEFb) and the 84 Mediator complex to promoters and enhancers, whilst its extra-terminal domain confers transcriptional 85 activation through the recruitment of CHD4, JMJD6, and NSD3 11,12 . 86 3 The CdLS-associated BRD4 missense mutation is in the ...

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The Emerging Role of Cohesin in the DNA Damage Response

Cited by 68 publications

References 220 publications

Reduced Expression of Genes Regulating Cohesion Induces Chromosome Instability that May Promote Cancer and Impact Patient Outcomes

Reduced Expression of Genes Regulating Cohesion Induces Chromosome Instability that May Promote Cancer and Impact Patient Outcomes

Systematic identification of cancer cell vulnerabilities to natural killer cell-mediated immune surveillance

Cornelia-de Lange syndrome-associated mutations cause a DNA damage signalling and repair defect

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