Journal
GENES & DEVELOPMENT
Volume 33, Issue 5-6, Pages 310-332Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.314633.118
Keywords
BRN2; POU3F2; Ku80; melanoma; somatic mutation burden; BCL2; apoptosis; nonhomologous end-joining
Categories
Funding
- Canada Foundation for Innovation funding
- Ontario Genomics [OGI-139]
- Wellcome Trust fellowship [106288/Z/14/Z]
- Ludwig Institute for Cancer Research
- National Institutes of Health [PO1 CA128814-06A1]
- Canadian Institutes of Health Research (CIHR) Foundation grant [FDN 143301]
- National Institute for Health Research Biomedical Research Centre, Oxford
- Wellcome Trust Seed Award in Science [204562/Z/16/Z]
- Universidad Nacional Autonoma de Mexico PAPIIT grant [IA200318]
- Deutsche Forschungsgemeinschaft [392470008]
- Cancer Research Society [22779]
- Junior 1 salary award from the Fonds de Recherche duQuebec-Sante (FRQ-S)
- Fondation ARC project labellise
- La Ligue National Contre le Cancer
- Institut National du Cancer
- Institut Thematique Multi-Organisme Cancer
- CIHR Foundation grant
- Wellcome Trust [204562/Z/16/Z, 106288/Z/14/Z] Funding Source: Wellcome Trust
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available