DYNLL1 binds to MRE11 to limit DNA end resection in BRCA1-deficient cells

Limited DNA end resection is the key to impaired homologous recombination in BRCA1 -mutant cancer cells. Here, using a loss-of-function CRISPR screen, we identify DYNLL1 as an inhibitor of DNA end resection. The loss of DYNLL1 enables DNA end resection and restores homologous recombination in BRCA1...

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Published in:	Nature (London) Vol. 563; no. 7732; pp. 522 - 526
Main Authors:	He, Yizhou Joseph, Meghani, Khyati, Caron, Marie-Christine, Yang, Chunyu, Ronato, Daryl A., Bian, Jie, Sharma, Anchal, Moore, Jessica, Niraj, Joshi, Detappe, Alexandre, Doench, John G., Legube, Gaelle, Root, David E., D’Andrea, Alan D., Drané, Pascal, De, Subhajyoti, Konstantinopoulos, Panagiotis A., Masson, Jean-Yves, Chowdhury, Dipanjan
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01.11.2018 Nature Publishing Group
Subjects:	13/1 13/106 13/109 13/89 14/19 14/63 38/77 631/337/1427/2190 631/67/1059/2326 Adenosine diphosphate Biochemistry, Molecular Biology Biotechnology BRCA genes BRCA1 protein BRCA1 Protein - deficiency BRCA1 Protein - genetics Breast cancer Cancer Cancer cells Cancer genetics Cancer therapies Cell Line, Tumor Chemotherapy Chromosome Aberrations Chromosome abnormalities CRISPR CRISPR-Cas Systems - genetics Cytoplasmic Dyneins - metabolism Deoxyribonucleic acid DNA DNA - metabolism DNA damage DNA Damage - drug effects DNA helicase DNA methylation DNA repair Drug resistance Drug Resistance, Neoplasm - drug effects Drugs Endonuclease FDA approval Female Gene Editing Gene expression Genes Genes, BRCA1 Genetic research Genomes Genomic Instability - drug effects Homologous recombination Homologous Recombination - drug effects Homology Humanities and Social Sciences Humans Ionizing radiation Lesions Life Sciences Molecular biology Monosaccharides MRE11 Homologue Protein - metabolism MRE11 protein multidisciplinary Mutation Nucleases Ovarian cancer Ovarian carcinoma Ovarian Neoplasms - genetics Ovarian Neoplasms - pathology Platinum Platinum - pharmacology Poly(ADP-ribose) Poly(ADP-ribose) polymerase Poly(ADP-ribose) Polymerase Inhibitors - pharmacology Protein Binding Proteins Recombinational DNA Repair - drug effects Ribose Science Science (multidisciplinary) Surgery Transcription Factors - metabolism Somatic Structural Variants Homologous Recombination-mediated Repair BRCA Mutant Cells Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) High-grade Serous Ovarian Carcinoma (HGSOC)
ISSN:	0028-0836, 1476-4687, 1476-4687
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Summary:	Limited DNA end resection is the key to impaired homologous recombination in BRCA1 -mutant cancer cells. Here, using a loss-of-function CRISPR screen, we identify DYNLL1 as an inhibitor of DNA end resection. The loss of DYNLL1 enables DNA end resection and restores homologous recombination in BRCA1 -mutant cells, thereby inducing resistance to platinum drugs and inhibitors of poly(ADP-ribose) polymerase. Low BRCA1 expression correlates with increased chromosomal aberrations in primary ovarian carcinomas, and the junction sequences of somatic structural variants indicate diminished homologous recombination. Concurrent decreases in DYNLL1 expression in carcinomas with low BRCA1 expression reduced genomic alterations and increased homology at lesions. In cells, DYNLL1 limits nucleolytic degradation of DNA ends by associating with the DNA end-resection machinery (MRN complex, BLM helicase and DNA2 endonuclease). In vitro, DYNLL1 binds directly to MRE11 to limit its end-resection activity. Therefore, we infer that DYNLL1 is an important anti-resection factor that influences genomic stability and responses to DNA-damaging chemotherapy. DYNLL1 antagonizes end resection of DNA double-strand breaks, thereby inhibiting homologous repair, and the loss of DYNLL1 correlates with poor progression-free survival of patients with BRCA1 -mutant ovarian cancer.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 PMCID: PMC7155769 Author Contributions YJH and D.C designed the study with input from PK and ADD. YJH and KM performed most of the cell-based experiments with assistance from CY, JB, JM, and PD. AD did the statistical analysis of images. MCC, DAR and JN conducted the in vitro studies under JYM’s supervision. GL provided the guidance and reagents on the AsiSI system. JD and DR provided all the reagents and the analysis of CRISPR library. AS did statistical and computational analysis of clinical data under SD’s guidance. D.C. wrote the manuscript with input from PK and ADD.
ISSN:	0028-0836 1476-4687 1476-4687
DOI:	10.1038/s41586-018-0670-5