Functional Radiogenetic Profiling Implicates ERCC6L2 in Non-homologous End Joining
Paola Francica,
Merve Mutlu,
Vincent A. Blomen,
Catarina Oliveira,
Zuzanna Nowicka,
Anika Trenner,
Nora M. Gerhards,
Peter Bouwman,
Elmer Stickel,
Maarten L. Hekkelman,
Lea Lingg,
Ismar Klebic,
Marieke van de Ven,
Renske de Korte-Grimmerink,
Denise Howald,
Jos Jonkers,
Alessandro A. Sartori,
Wojciech Fendler,
J. Ross Chapman,
Thijn Brummelkamp,
Sven Rottenberg
Affiliations
Paola Francica
Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland
Merve Mutlu
Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland
Vincent A. Blomen
Division of Biochemistry, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands; Oncode Institute, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands
Catarina Oliveira
Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK
Zuzanna Nowicka
Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215 Lodz, Poland
Anika Trenner
Institute of Molecular Cancer Research, University of Zurich, 8057 Zurich, Switzerland
Nora M. Gerhards
Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland
Peter Bouwman
Oncode Institute, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands; Division of Molecular Pathology, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands
Elmer Stickel
Division of Biochemistry, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands; Oncode Institute, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands
Maarten L. Hekkelman
Division of Biochemistry, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands; Oncode Institute, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands
Lea Lingg
Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland
Ismar Klebic
Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland
Marieke van de Ven
Mouse Clinic for Cancer and Aging Research (MCCA), Preclinical Intervention Unit, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands
Renske de Korte-Grimmerink
Mouse Clinic for Cancer and Aging Research (MCCA), Preclinical Intervention Unit, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands
Denise Howald
Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland
Jos Jonkers
Oncode Institute, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands; Division of Molecular Pathology, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands
Alessandro A. Sartori
Institute of Molecular Cancer Research, University of Zurich, 8057 Zurich, Switzerland
Wojciech Fendler
Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215 Lodz, Poland; Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
J. Ross Chapman
Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK
Thijn Brummelkamp
Division of Biochemistry, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands; Oncode Institute, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands
Sven Rottenberg
Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland; Division of Molecular Pathology, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands; Bern Center for Precision Medicine, University of Bern, 3012 Bern, Switzerland; Corresponding author
Summary: Using genome-wide radiogenetic profiling, we functionally dissect vulnerabilities of cancer cells to ionizing radiation (IR). We identify ERCC6L2 as a major determinant of IR response, together with classical DNA damage response genes and members of the recently identified shieldin and CTC1-STN1-TEN1 (CST) complexes. We show that ERCC6L2 contributes to non-homologous end joining (NHEJ), and it may exert this function through interactions with SFPQ. In addition to causing radiosensitivity, ERCC6L2 loss restores DNA end resection and partially rescues homologous recombination (HR) in BRCA1-deficient cells. As a consequence, ERCC6L2 deficiency confers resistance to poly (ADP-ribose) polymerase (PARP) inhibition in tumors deficient for both BRCA1 and p53. Moreover, we show that ERCC6L2 mutations are found in human tumors and correlate with a better overall survival in patients treated with radiotherapy (RT); this finding suggests that ERCC6L2 is a predictive biomarker of RT response.
