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The abolition of DFF40 expression in Jurkat cells significantly impairs histone H2AX phosphorylation following etoposide and cytarabine treatments. Etoposide exposure in DFF40 deficient cells induces higher mortality levels and downregulation of Bcl-xL cells compared to DFF40 expressing T cells. DFF40 deficient cells exposed to cytarabine present lower phosphatidylserine translocation levels to the outer cell membrane layer. methotrexate, 6-mercaptopurine and cytarabine) and surprisingly, they are more sensitive to TOP2 inhibitors ( e.g. DFF40 deficient cells show chemoresistance to antimetabolites ( e.g. CRISPR-cas9 generated DFF40 knockout (DFF40 KO) stable Jurkat cells and wild-type (DFF40 WT) cells were treated with different antimetabolites and topoisomerase II (TOP2) inhibitors, and cell viability was subsequently assessed. In this study, we sought to determine if a DFF40 deficiency in Jurkat T cells could impact the sensitivity to conventional chemotherapy drugs.
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DFF40 is the endonuclease responsible of DNA fragmentation during apoptosis. In concordance with these observations, in this study, we showed that DFF40 gene is also downregulated in breast, endocervical, ovarian, lung, pancreas and glioblastomas. Glioblastomas and uterine leiomyosarcomas have been shown to have a downregulation of DFF40 expression, conferring a poor patient prognosis. The DNA fragmentation factor 40 (DFF40) has been gaining interest regarding cancer cell response to chemotherapy and patient outcomes. Many mutations have been linked to drug resistance. In untreated cells, procaspase-3 and ICAD were detected at both cytosolic and nucleoplasmic fractions. The regulation of the apoptotic pathway is one of the most studied mechanisms regarding cancer cell resistance. Due to the relevance of DFF40/CAD cytosolic pool for oligonucleosomal DNA hydrolysis during apoptosis, 14 we evaluated caspase-3, ICAD, and DFF40/CAD intracellular distribution in cytosolic, nucleoplasmic, and chromatin-enriched fractions.