BRCA2 abrogation triggers innate immune responses potentiated by treatment with PARP inhibitors

• Published in: Nature communications Vol. 10; no. 1; pp. 3143 - 13
• Main Authors: Reisländer, Timo, Lombardi, Emilia Puig, Groelly, Florian J., Miar, Ana, Porru, Manuela, Di Vito, Serena, Wright, Benjamin, Lockstone, Helen, Biroccio, Annamaria, Harris, Adrian, Londoño-Vallejo, Arturo, Tarsounas, Madalena
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17-07-2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/106; 38; 38/91; 631/337/1427; 631/67/1347; Animals; BRCA2 protein; BRCA2 Protein - genetics; Breast; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - immunology; Cancer; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - immunology; Cell cycle; Cell Cycle - drug effects; Cell death; Cell Line, Tumor; Clonal deletion; Colorectal Neoplasms - genetics; Colorectal Neoplasms - immunology; Deactivation; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA Damage; DNA Repair; Female; Gene Deletion; Gene expression; Gene Expression Regulation, Neoplastic; Genes; Genomes; Humanities and Social Sciences; Humans; Immune response; Immunity, Innate; Inactivation; Inhibitors; Innate immunity; Interferon; Life Sciences; Mice, SCID; multidisciplinary; Mutation; Ovarian cancer; Phthalazines - pharmacology; Piperazines - pharmacology; Poly(ADP-ribose) polymerase; Ribonucleic acid; RNA; Science; Science (multidisciplinary); Transcription activation; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-11048-5

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.
BRCA2 plays important roles in cell physiology by promoting DNA replication and DNA double-strand breaks repair. Here the authors, reveal the impact of BRCA2 depletion on the cell transcriptional program with activation of the innate immune response that is potentiated by PARP inhibitor treatments.