Rad9A Is Required for G2 Decatenation Checkpoint and to Prevent Endoreduplication in Response to Topoisomerase II Inhibition

Card, Deborah A. Greer; Sierant, Megan L.; Davey, Scott

doi:10.1074/jbc.m109.096156

Cited by 17 publications

(12 citation statements)

References 38 publications

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“…We also noted increased levels of cytoplasmic cyclin B1 in ARID1A −/− cells (Supplementary Fig. 4H) a phenotype associated with initiation of a G 2 /M cell cycle checkpoint36. Collectively, this data suggested that loss of ARID1A caused a reduced rate of S phase progression and an increased utilization of a G 2 /M cell cycle checkpoint.…”

Section: Resultsmentioning

confidence: 54%

ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A

et al. 2016

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Identifying genetic biomarkers of synthetic lethal drug sensitivity effects provides one approach to the development of targeted cancer therapies. Mutations in ARID1A represent one of the most common molecular alterations in human cancer, but therapeutic approaches that target these defects are not yet clinically available. We demonstrate that defects in ARID1A sensitize tumour cells to clinical inhibitors of the DNA damage checkpoint kinase, ATR, both in vitro and in vivo. Mechanistically, ARID1A deficiency results in topoisomerase 2A and cell cycle defects, which cause an increased reliance on ATR checkpoint activity. In ARID1A mutant tumour cells, inhibition of ATR triggers premature mitotic entry, genomic instability and apoptosis. The data presented here provide the pre-clinical and mechanistic rationale for assessing ARID1A defects as a biomarker of single-agent ATR inhibitor response and represents a novel synthetic lethal approach to targeting tumour cells.

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Section: Resultsmentioning

confidence: 54%

ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A

et al. 2016

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“…G2/M checkpoint was examined by standard methods after treating ESCs with etoposide (Greer Card et al, 2010). …”

Section: Methodsmentioning

confidence: 99%

Filia Is an ESC-Specific Regulator of DNA Damage Response and Safeguards Genomic Stability

et al. 2015

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Summary Pluripotent stem cells (PSCs) hold great promise in cell-based therapy, but the genomic instability seen in culture hampers full application. Greater understanding of the factors that regulate genomic stability in PSCs could help address this issue. Here we describe the identification of Filia as a specific regulator of genomic stability in mouse embryonic stem cells (ESCs). Filia expression is induced by genotoxic stress. Filia promotes centrosome integrity and regulates DNA damage response (DDR) through multiple pathways, including DDR signaling, cell cycle checkpoints and damage repair, ESC differentiation and apoptosis. Filia depletion causes ESC genomic instability, induces resistance to apoptosis and promotes malignant transformation. As part of its role in the DDR, Filia interacts with PARP1 and stimulates its enzymatic activity. Filia also constitutively resides on centrosomes and translocates to DNA damage sites and mitochondria, consistent with its multifaceted roles in regulating centrosome integrity, damage repair and apoptosis.

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“…The barely studied KIAA0319L and transmembrane protein clarin 3 (CLRN3) as well as COX6A1, which is involved in oxidative phosphorylation, affect recurrence rate but for now we cannot connect these proteins mechanistically to disease progression. Finally, the RAD9A checkpoint protein is required for proper localization of topoisomerase II‐binding protein 1 (TopBP1) regulating cell cycle checkpoints, DNA repair, telomere stability and apoptosis (Greer Card et al., 2010; Broustas and Lieberman, 2012; Lieberman et al., 2011) thereby preserving genomic integrity in all types of DNA aberrations (Greer Card et al., 2010; Broustas and Lieberman, 2012; Lieberman et al., 2011). In the current study, RAD9A was relatively downregulated in patients with early recurrences suggesting loss of genomic integrity is another contributing factor to recurrence (Broustas and Lieberman, 2012).…”

Section: Discussionmentioning

confidence: 99%

mRNA expression profiles of colorectal liver metastases as a novel biomarker for early recurrence after partial hepatectomy

et al. 2016

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SurgeryBiomarker mRNA Prognostic value A B S T R A C TBackground: Identification of specific risk groups for recurrence after surgery for isolated colorectal liver metastases (CRLM) remains challenging due to the heterogeneity of the disease. Classical clinicopathologic parameters have limited prognostic value. The aim of this study was to identify a gene expression signature measured in CRLM discriminating early from late recurrence after partial hepatectomy. Methods: CRLM from two patient groups were collected: I) with recurrent disease 12 months after surgery (N ¼ 33), and II) without recurrences and disease free for !36 months (N ¼ 30). The patients were clinically homogeneous; all had a low clinical risk score (0e2) and did not receive (neo-) adjuvant chemotherapy. Total RNA was hybridised to Illumina arrays, and processed for analysis. A leave-one-out cross validation (LOOCV) analysis was performed to identify a prognostic gene expression signature. Results: LOOCV yielded an 11-gene profile with prognostic value in relation to recurrent disease 12 months after partial hepatectomy. This signature had a sensitivity of 81.8%, with a specificity of 66.7% for predicting recurrences ( 12 months) versus no recurrences for at least 36 months after surgery (X 2 P < 0.0001). Conclusion:The current study yielded an 11-gene signature at mRNA level in CRLM discriminating early from late or no relapse after partial hepatectomy.

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Rad9A Is Required for G2 Decatenation Checkpoint and to Prevent Endoreduplication in Response to Topoisomerase II Inhibition

Cited by 17 publications

References 38 publications

ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A

ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A

Filia Is an ESC-Specific Regulator of DNA Damage Response and Safeguards Genomic Stability

mRNA expression profiles of colorectal liver metastases as a novel biomarker for early recurrence after partial hepatectomy

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