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03 01, 2019;33 (5-6): 310-332.

BRN2 suppresses apoptosis, reprograms DNA damage repair, and is associated with a high somatic mutation burden in melanoma.

Katharine Herbert, Romuald Binet, Jean-Philippe Lambert, Pakavarin Louphrasitthiphol, Halime Kalkavan, Laura Sesma-Sanz, Carla Daniela Robles-Espinoza, Sovan Sarkar, Eda Suer, Sarah Andrews, Jagat Chauhan, Nicola D Roberts, Mark R Middleton, Anne-Claude Gingras, Jean-Yves Masson, Lionel Larue, Paola Falletta, Colin R Goding
Author Information
  1. Katharine Herbert: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Headington, Oxford OX3 7DQ, United Kingdom.
  2. Romuald Binet: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Headington, Oxford OX3 7DQ, United Kingdom.
  3. Jean-Philippe Lambert: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
  4. Pakavarin Louphrasitthiphol: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Headington, Oxford OX3 7DQ, United Kingdom.
  5. Halime Kalkavan: Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
  6. Laura Sesma-Sanz: Genome Stability Laboratory, CHU de Oncology Division, Québec Research Center, Québec City, Quebec G1R 3S3, Canada.
  7. Carla Daniela Robles-Espinoza: Laboratorio Internacional de Investigación Sobre el Genoma Humano, Universidad Nacional Autónoma de México, Santiago de Querétaro 76230, Mexico.
  8. Sovan Sarkar: Department of Oncology, University of Oxford, Headington, Oxford OX3 7DQ, United Kingdom.
  9. Eda Suer: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Headington, Oxford OX3 7DQ, United Kingdom.
  10. Sarah Andrews: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Headington, Oxford OX3 7DQ, United Kingdom.
  11. Jagat Chauhan: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Headington, Oxford OX3 7DQ, United Kingdom.
  12. Nicola D Roberts: The Cancer Genome Project, The Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, United Kingdom.
  13. Mark R Middleton: Department of Oncology, University of Oxford, Headington, Oxford OX3 7DQ, United Kingdom.
  14. Anne-Claude Gingras: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
  15. Jean-Yves Masson: Genome Stability Laboratory, CHU de Oncology Division, Québec Research Center, Québec City, Quebec G1R 3S3, Canada.
  16. Lionel Larue: Institut Curie, PSL Research University, Normal and Pathological Development of Melanocytes, U1021, Institut National de la Santé et de la Recherche Médicale (INSERM), 91405 Orsay, France.
  17. Paola Falletta: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Headington, Oxford OX3 7DQ, United Kingdom.
  18. Colin R Goding: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Headington, Oxford OX3 7DQ, United Kingdom.
PMID: 30804224 DOI: 10.1101/gad.314633.118

Abstract

Whether cell types exposed to a high level of environmental insults possess cell type-specific prosurvival mechanisms or enhanced DNA damage repair capacity is not well understood. BRN2 is a tissue-restricted POU domain transcription factor implicated in neural development and several cancers. In melanoma, BRN2 plays a key role in promoting invasion and regulating proliferation. Here we found, surprisingly, that rather than interacting with transcription cofactors, BRN2 is instead associated with DNA damage response proteins and directly binds PARP1 and Ku70/Ku80. Rapid PARP1-dependent BRN2 association with sites of DNA damage facilitates recruitment of Ku80 and reprograms DNA damage repair by promoting Ku-dependent nonhomologous end-joining (NHEJ) at the expense of homologous recombination. BRN2 also suppresses an apoptosis-associated gene expression program to protect against UVB-, chemotherapy- and vemurafenib-induced apoptosis. Remarkably, BRN2 expression also correlates with a high single-nucleotide variation prevalence in human melanomas. By promoting error-prone DNA damage repair via NHEJ and suppressing apoptosis of damaged cells, our results suggest that BRN2 contributes to the generation of melanomas with a high mutation burden. Our findings highlight a novel role for a key transcription factor in reprogramming DNA damage repair and suggest that BRN2 may impact the response to DNA-damaging agents in BRN2-expressing cancers.

Keywords

BCL2 BRN2 Ku80 POU3F2 apoptosis melanoma nonhomologous end-joining somatic mutation burden

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Grants

  1. P01 CA128814/NCI NIH HHS
  2. 106288/Z/14/Z/Wellcome Trust
  3. FDN 143301/CIHR
  4. 204562/Z/16/Z/Wellcome Trust
  5. /Wellcome Trust

MeSH Term

Apoptosis
Cell Line, Tumor
DNA End-Joining Repair
Gene Expression Regulation, Neoplastic
Homeodomain Proteins
Humans
Ku Autoantigen
Melanoma
Mutation
POU Domain Factors
Poly (ADP-Ribose) Polymerase-1
Protein Binding
Protein Domains
Protein Transport

Chemicals

Homeodomain Proteins
POU Domain Factors
transcription factor Brn-2
Poly (ADP-Ribose) Polymerase-1
Ku Autoantigen
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Links to CNCB-NGDC Resources

GEN: GEND000027 (The study of the role of POU3F2 in response to UVB treatment)

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