Repression of Transcription at DNA Breaks Requires Cohesin throughout Interphase and Prevents Genome Instability

Meisenberg, Cornelia; Pinder, Sarah I.; Hopkins, Suzanna R.; Wooller, Sarah K.; Benstead-Hume, Graeme; Pearl, Frances M. G.; Jeggo, Penny A.; Downs, Jessica A.

doi:10.1016/j.molcel.2018.11.001

Cited by 96 publications

(83 citation statements)

References 45 publications

(69 reference statements)

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“…DSBs also induce transcriptional repression [9][10][11][12][13][14] . This effect has first been described in the nucleoli where the ribosomal gene (rDNA) arrays that make up for the highest transcribed sites in the human genome are located 9 .…”

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confidence: 99%

Treacle controls the nucleolar response to rDNA breaks via TOPBP1 recruitment and ATR activation

et al. 2020

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Induction of DNA double-strand breaks (DSBs) in ribosomal DNA (rDNA) repeats is associated with ATM-dependent repression of ribosomal RNA synthesis and large-scale reorganization of nucleolar architecture, but the signaling events that regulate these responses are largely elusive. Here we show that the nucleolar response to rDNA breaks is dependent on both ATM and ATR activity. We further demonstrate that ATM-and NBS1-dependent recruitment of TOPBP1 in the nucleoli is required for inhibition of ribosomal RNA synthesis and nucleolar segregation in response to rDNA breaks. Mechanistically, TOPBP1 recruitment is mediated by phosphorylation-dependent interactions between three of its BRCT domains and conserved phosphorylated Ser/Thr residues at the C-terminus of the nucleolar phosphoprotein Treacle. Our data thus reveal an important cooperation between TOPBP1 and Treacle in the signaling cascade that triggers transcriptional inhibition and nucleolar segregation in response to rDNA breaks.

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confidence: 99%

Treacle controls the nucleolar response to rDNA breaks via TOPBP1 recruitment and ATR activation

et al. 2020

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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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“…Taken together, these observations indicate a possible multi-modal ARID2 inactivation in cancers, which needs to be explored in greater detail. In addition to its well documented role in regulating gene expression 50, 51 , ARID2 plays a dual role in DNA repair by a) interacting with RAD1 to promote homology directed repair 11 and b) promoting transcriptional repression in double strand break repair 37 . Considering the recent interest to develop targeted therapy against SWI/SNF deficient cancers 44 , it is interesting to determine whether the tumor suppressor role of ARID2 in CRC is dependent on its transcription regulatory or DNA repair function(s).…”

Section: Discussionmentioning

confidence: 99%

Exome sequencing identifies ARID2 as a novel tumor suppressor in early-onset sporadic rectal cancer

Bala

Singh

Kavadipula

et al. 2020

Preprint

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24Early-onset sporadic rectal cancer (EOSRC) is a unique and predominant colorectal cancer 25 (CRC) subtype in India. In order to understand the tumorigenic process in EOSRC, we 26 performed whole exome sequencing of 47 microsatellite stable EOSRC samples. Signature 1 was 27 the predominant mutational signature in EOSRC, as previously shown in other CRC exome 28 studies. More importantly, we identified TP53, KRAS, APC, PIK3R1 and SMAD4 as significantly 29 mutated (q<0.1) and ARID1A and ARID2 as near-significantly mutated (restricted hypothesis 30 testing; q<0.1) candidate drivers. Unlike the other candidates, the tumorigenic potential of 31 ARID2, encoding a component of the SWI/SNF chromatin remodeling complex, is largely 32 unexplored in CRC. shRNA mediated ARID2 knockdown performed in two different CRC cell 33 lines resulted in significant alterations in transcript levels of cancer-related target genes. More 34 importantly, ARID2 knockdown promoted several tumorigenic features including cell viability, 35proliferation, ability to override contact inhibition of growth, and migration besides significantly 36 increasing tumor formation ability in nude mice. The observed gain in tumorigenic features were 37 rescued upon ectopic expression of ARID2. Analyses of the TCGA CRC dataset revealed poorer 38 survival in patients with ARID2 alterations. We therefore propose ARID2 as a novel tumor 39 suppressor in CRC. 40 41 Keywords: Rectal cancer; mutational signatures; tumor suppressor; cancer driver genes; ARID2 42 4 genes/pathways 28, 42 . We now report identification of ARID2 as a novel tumor suppressor for 66 CRC based on a whole exome sequencing analysis of EOSRC samples. 67 68Results 69 Whole Exome sequencing reveals known and novel characteristics in EOSRC 70To identify molecular alterations underlying rectal adenocarcinoma, we performed whole exome 71 sequencing analysis of 47 carefully selected well annotated microsatellite stable (MSS) rectal 72 tumor and matched normal sample pairs (EOSRC-IN). All samples were from patients aged 73 below 61 years (average 46 years; range 22-60; Table S1). Sequence data analyses and variant 74 calling (see Methods and Figure S1) identified 17,471 substitutions and 1,432 small insertions 75 and deletions (indels) ( Table S2A). The number of substitutions predominated over indels across 76 all samples with a mean rate (per megabase (MB)) of 6.4 (range 1-35 per sample) for 77 substitutions and 0.5 (range 0-2.35 per sample) for indels ( Figure 1a). Five samples (EOSRC-IN-78 1095, 2575, 2603, 2643 and 2669) showed a significantly higher mutation rate (>12/MB) and 79 can be considered to exhibit a 'Hypermutator-like condition' as described in The Cancer Genome 80Atlas (TCGA) study on CRC 6 . Given that all samples were MSS (status of the 'hypermutator-81 like' samples was re-confirmed using the same DNA sample that was used for exome 82 sequencing), it is surprising to find a high mutation rate. The mean rate for substitutions and 83 indels in non-hypermutated (excluding the 'hypermu...

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Repression of Transcription at DNA Breaks Requires Cohesin throughout Interphase and Prevents Genome Instability

Cited by 96 publications

References 45 publications

Treacle controls the nucleolar response to rDNA breaks via TOPBP1 recruitment and ATR activation

Treacle controls the nucleolar response to rDNA breaks via TOPBP1 recruitment and ATR activation

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

Exome sequencing identifies ARID2 as a novel tumor suppressor in early-onset sporadic rectal cancer

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