A Genome-wide CRISPR Screen Identifies CDC25A as a Determinant of Sensitivity to ATR Inhibitors

Ruíz, Sergio; Mayor‐Ruiz, Cristina; Lafarga, Vanesa; Murga, Matilde; Vega-Sendino, María; Ortega, Sagrario; Fernández-Capetillo, Óscar

doi:10.1016/j.molcel.2016.03.006

Cited by 169 publications

(179 citation statements)

References 35 publications

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“…Over the last 3 years, CRISPR-Cas9 has been applied to mammalian screens, including screens to identify mechanisms of resistance or enhanced sensitivity to drugs (9,13), to identify mediators of immune response (14), and to identify enhancer elements (15). To date, however, this approach has not been systematically Pharmacologically difficult targets, such as MYC transcription factors, represent a major challenge in cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

CRISPR-Cas9 screen reveals a MYCN-amplified neuroblastoma dependency on EZH2

Chen

Alexe

Dharia

et al. 2017

Journal of Clinical Investigation

123

105

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Section: Introductionmentioning

confidence: 99%

CRISPR-Cas9 screen reveals a MYCN-amplified neuroblastoma dependency on EZH2

Chen

Alexe

Dharia

et al. 2017

Journal of Clinical Investigation

123

105

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“…Likewise, the toxicity of chemical inhibitors of ATR is higher in cells lacking p53 (10, 15, 16). This p53-independent cell killing by ATR inhibitors is linked to their capacity to induce the accumulation of DNA replication stress and premature mitotic entry, activities that are unrelated to p53 functions (17, 18). Hence, ATR inhibitors offer an alternative for the elimination of p53-deficient tumors.…”

Section: Introductionmentioning

confidence: 99%

Targeting the kinase activities of ATR and ATM exhibits antitumoral activity in mouse models of MLL -rearranged AML

et al. 2016

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Among the various subtypes of Acute Myeloid Leukemia (AML), those with chromosomal rearrangements of the MLL oncogene (AML-MLL) have a poor prognosis. AML-MLL tumor cells are resistant to current genotoxic therapies due to an attenuated response by p53, which induces cell cycle arrest and apoptosis in response to DNA damage. In addition to chemicals that damage DNA, efforts have focused on targeting DNA repair enzymes as a general chemotherapeutic approach to cancer treatment. Here, we found that inhibition of the kinase ATR, which is the primary sensor of DNA replication stress, induced chromosomal breakage and death of mouse AMLMLL cells (with an MLL-ENL fusion and a constitutively active N-RAS) independently of p53. Moreover, ATR inhibition as a single agent exhibited antitumoral activity, both reducing tumor burden after establishment and preventing tumors from growing, in an immunocompetent allograft mouse model of AMLMLL and in xenografts of a human AML-MLL cell line. We also found that inhibition of ATM, a kinase that senses DNA double-strand breaks, also promoted the survival of the AMLMLL mice. Collectively, these data indicated that ATR and ATM inhibition represent potential alternative therapeutic strategies for the treatment of AML, especially MLL-driven leukemias.

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“…p53 knockout mouse keratinocytes were generated by infecting mouse keratinocytes (Drosten et al, 2014) with lentiCas9-Blast (gift from Feng Zhang, Massachusetts Institute of Technology, Cambridge, MA) and a pKLV-U6gRNA-PGKpuro2ABFP vector expressing p53sgRNA [gift from Sergio Ruiz, Spanish National Cancer Research Centre (CNIO, Madrid, Spain) (Ruiz et al, 2016) and maintained in CNT-07 (CELLnTEC, Bern, Switzerland).…”

Section: Primary Cell Culture Transfection Viral Infection and Treamentioning

confidence: 99%

Clasp2 ensures mitotic fidelity and prevents differentiation of epidermal keratinocytes

Shahbazi¹,

Peña-Jiménez²,

Antonucci³

et al. 2017

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Epidermal homeostasis is tightly controlled by a balancing act of selfrenewal or terminal differentiation of proliferating basal keratinocytes. An increase in DNA content as a consequence of a mitotic block is a recognized mechanism underlying keratinocyte differentiation, but the molecular mechanisms involved in this process are not yet fully understood. Using cultured primary keratinocytes, here we report that the expression of the mammalian microtubule and kinetochoreassociated protein Clasp2 is intimately associated with the basal proliferative makeup of keratinocytes, and its deficiency leads to premature differentiation. Clasp2-deficient keratinocytes exhibit increased centrosomal numbers and numerous mitotic alterations, including multipolar spindles and chromosomal misalignments that overall result in mitotic stress and a high DNA content. Such mitotic block prompts premature keratinocyte differentiation in a p53-dependent manner in the absence of cell death. Our findings reveal a new role for Clasp2 in governing keratinocyte undifferentiated features and highlight the presence of surveillance mechanisms that prevent cell cycle entry in cells that have alterations in the DNA content.

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A Genome-wide CRISPR Screen Identifies CDC25A as a Determinant of Sensitivity to ATR Inhibitors

Cited by 169 publications

References 35 publications

CRISPR-Cas9 screen reveals a MYCN-amplified neuroblastoma dependency on EZH2

CRISPR-Cas9 screen reveals a MYCN-amplified neuroblastoma dependency on EZH2

Targeting the kinase activities of ATR and ATM exhibits antitumoral activity in mouse models of MLL -rearranged AML

Clasp2 ensures mitotic fidelity and prevents differentiation of epidermal keratinocytes

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