CHD4 regulates the DNA damage response and RAD51 expression in glioblastoma View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-12

AUTHORS

Lisa D. McKenzie, John W. LeClair, Kayla N. Miller, Averey D. Strong, Hilda L. Chan, Edward L. Oates, Keith L. Ligon, Cameron W. Brennan, Milan G. Chheda

ABSTRACT

Glioblastoma (GBM) is a lethal brain tumour. Despite therapy with surgery, radiation, and alkylating chemotherapy, most people have recurrence within 6 months and die within 2 years. A major reason for recurrence is resistance to DNA damage. Here, we demonstrate that CHD4, an ATPase and member of the nucleosome remodelling and deactetylase (NuRD) complex, drives a component of this resistance. CHD4 is overexpressed in GBM specimens and cell lines. Based on The Cancer Genome Atlas and Rembrandt datasets, CHD4 expression is associated with poor prognosis in patients. While it has been known in other cancers that CHD4 goes to sites of DNA damage, we found CHD4 also regulates expression of RAD51, an essential component of the homologous recombination machinery, which repairs DNA damage. Correspondingly, CHD4 suppression results in defective DNA damage response in GBM cells. These findings demonstrate a mechanism by which CHD4 promotes GBM cell survival after DNA damaging treatments. Additionally, we found that CHD4 suppression, even in the absence of extrinsic treatment, cumulatively increases DNA damage. Lastly, we found that CHD4 is dispensable for normal human astrocyte survival. Since standard GBM treatments like radiation and temozolomide chemotherapy create DNA damage, these findings suggest an important resistance mechanism that has therapeutic implications. More... »

PAGES

4444

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41598-019-40327-w

DOI

http://dx.doi.org/10.1038/s41598-019-40327-w

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1112764135

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30872624


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