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

Yizhou Joseph He, Khyati Meghani, Marie-Christine Caron, Chunyu Yang, Daryl A. Ronato, Jie Bian, Anchal Sharma, Jessica Moore, Joshi Niraj, Alexandre Detappe, John G. Doench, Gaelle Legube, David E. Root, Alan D. D’Andrea, Pascal Drané, Subhajyoti De, Panagiotis A. Konstantinopoulos, Jean-Yves Masson and Dipanjan Chowdhury ()
Additional contact information
Yizhou Joseph He: Dana-Farber Cancer Institute, Harvard Medical School
Khyati Meghani: Dana-Farber Cancer Institute, Harvard Medical School
Marie-Christine Caron: HDQ Pavilion, Oncology Axis, Québec City
Chunyu Yang: Dana-Farber Cancer Institute, Harvard Medical School
Daryl A. Ronato: HDQ Pavilion, Oncology Axis, Québec City
Jie Bian: Dana-Farber Cancer Institute, Harvard Medical School
Anchal Sharma: Rutgers Cancer Institute of New Jersey
Jessica Moore: Dana-Farber Cancer Institute, Harvard Medical School
Joshi Niraj: Dana-Farber Cancer Institute, Harvard Medical School
Alexandre Detappe: Harvard Medical School
John G. Doench: Broad Institute of Harvard and MIT
Gaelle Legube: CNRS, Université de Toulouse, UT3
David E. Root: Broad Institute of Harvard and MIT
Alan D. D’Andrea: Dana-Farber Cancer Institute, Harvard Medical School
Pascal Drané: Dana-Farber Cancer Institute, Harvard Medical School
Subhajyoti De: Rutgers Cancer Institute of New Jersey
Panagiotis A. Konstantinopoulos: Harvard Medical School
Jean-Yves Masson: HDQ Pavilion, Oncology Axis, Québec City
Dipanjan Chowdhury: Dana-Farber Cancer Institute, Harvard Medical School

Nature, 2018, vol. 563, issue 7732, 522-526

Abstract: Abstract 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.

Keywords: Somatic Structural Variants; BRCA Mutant Cells; Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR); High-grade Serous Ovarian Carcinoma (HGSOC); Homologous Recombination-mediated Repair (search for similar items in EconPapers)
Date: 2018
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DOI: 10.1038/s41586-018-0670-5

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