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Heterozygous germline mutations in BRCA2 predispose to breast and ovarian cancer. Contrary to non-cancerous cells, where BRCA2 deletion causes cell cycle arrest or cell death, tumors carrying BRCA2 inactivation continue to proliferate. Here we set out to investigate adaptation to loss of BRCA2 focusing on genome-wide transcriptome alterations. Human cells in which BRCA2 expression is inhibited for 4 or 28 days are subjected to RNA-seq analyses revealing a biphasic response to BRCA2 abrogation. The early, acute response consists of downregulation of genes involved in cell cycle progression, DNA replication and repair and is associated with cell cycle arrest in G1. Surprisingly, the late, chronic response consists predominantly of upregulation of interferon-stimulated genes (ISGs). Activation of the cGAS-STING-STAT pathway detected in these cells further substantiates the concept that BRCA2 abrogation triggers cell-intrinsic immune signaling. Importantly, we find that treatment with PARP inhibitors stimulates the interferon response in cells and tumors lacking BRCA2.

Original publication

DOI

10.1038/s41467-019-11048-5

Type

Journal article

Journal

Nat Commun

Publication Date

17/07/2019

Volume

10

Keywords

Animals, BRCA2 Protein, Breast Neoplasms, Carcinoma, Non-Small-Cell Lung, Cell Cycle, Cell Line, Tumor, Colorectal Neoplasms, DNA Damage, DNA Repair, Female, Gene Deletion, Gene Expression Regulation, Neoplastic, Humans, Immunity, Innate, Mice, SCID, Phthalazines, Piperazines