The DNA2 nuclease/helicase is an estrogen-dependent gene mutated in breast and ovarian cancers

Abstract

Genomic instability, a hallmark of cancer, is commonly caused by failures in the DNA damage response. Here we conducted a bioinformatical screen to reveal DNA damage response genes that are upregulated by estrogen and highly mutated in breast and ovarian cancers. This screen identified 53 estrogen-dependent cancer genes, some of which are novel. Notably, the screen retrieved 9 DNA helicases as well as 5 nucleases. DNA2, which functions as both a helicase and a nuclease and plays a role in DNA repair and replication, was retrieved in the screen. Mutations in DNA2, found in estrogen-dependent cancers, are clustered in the helicase and nuclease domains, suggesting activity impairment. Indeed, we show that mutations found in ovarian cancers impair DNA2 activity. Depletion of DNA2 in cells reduces their tumorogenicity in mice. In human, high expression of DNA2 correlates with poor survival of estrogen receptor-positive patients but not of estrogen receptor-negative patients. We also demonstrate that depletion of DNA2 in cells reduces proliferation, while addition of estrogen restores proliferation. These findings suggest that cells responding to estrogen will proliferate despite being impaired in DNA2 activity, potentially promoting genomic instability and triggering cancer development.

Inhibition of DNA2 nuclease as a therapeutic strategy targeting replication stress in cancer cells

“…replication stress caused by the mec1-21 mutation 48 . Interestingly, similar to this observation in yeast cells, studies from our group and others have demonstrated that DNA2 is overexpressed in a broad spectrum of malignancies including breast cancer, ovarian cancer, lung cancer, prostate cancer, glioblastoma, pancreatic cancer, leukemia, colon cancer, melanoma, Lynch Syndrome, and hereditary nonpolyposis colorectal cancer 19,42,45 . DNA2 overexpression is needed for the tolerance of increased replication stress induced by oncogene activation such as H-Ras or cyclin E in osteosarcoma and breast cancer cells, and partial depletion of DNA2 reduces the tumorigenicity of breast cancer cells 42 .…”

Replication intermediates that escape Dna2 activity are processed by Holliday junction resolvase Yen1

“…Loss and overexpression of DNA2 has been observed in human cancers and cancer cell lines125758, while haploinsufficiency promotes cancer formation in heterozygous DNA2 -knockout mice9. This suggests a complex role in cancer, where genome instability caused by impaired DNA2 function may drive tumorigenesis, whereas upregulation of DNA2 may help cancer cells to survive continuous DNA replication stress.…”

RNA sequencing-based cell proliferation analysis across 19 cancers identifies a subset of proliferation-informative cancers with a common survival signature

“…CRYL1 has been shown to regulate G 2 -M phase transition and expression has been linked to patient prognosis [53]. DNA2 is a DNA helicase that plays an important role in processing Okazaki fragments during DNA replication and DNA2 expression has been correlated to patient survival [54]. HJURP is a histone chaperone shown to play a role in the progression of gliomas and breast tumors [55,56].…”