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.
Highlights
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
In melanoma BRN2 regulates proliferation (Goodall et al 2004a) and promotes invasion (Goodall et al 2008; Arozarena et al 2011; Thurber et al 2011; Fane et al 2017; Zeng et al 2018). This is reflected in the correlation between BRN2 expression in The Cancer Genome Atlas (TCGA) melanoma cohort and the well-characterized melanoma-associated Verfaillie (Verfaillie et al 2015) invasive gene expression signature, whereas BRN2 is anticorrelated with the Verfaillie proliferative gene expression signature (Supplemental Fig. S1A)
We found no correlation between single nucleotide variant (SNV) load and the expression of the BRN2-related factors BRN3a (POU4f1) (Supplemental Fig. S7A), BRN3b (POU4f2) which was poorly expressed in most melanomas (Supplemental Fig. S7B), microphthalmia-associated transcription factor (MITF) (Supplemental Fig. S7C), or a gene set comprising well-characterized MITF-target genes as a surrogate marker for MITF activity (Supplemental Fig. S7D)
Summary
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. While this is not a major issue for short-lived keratinocytes, for long-lived cells at the basal layer of the epidermis accumulation of DNA damage can lead to malignant transformation This is reflected in the frequently very high mutational burden of cutaneous melanoma (Hodis et al 2012; Krauthammer et al 2012; Alexandrov et al 2013), a highly. Lineage identity is determined by the activity of tissuerestricted transcription factor binding to sequence elements within genes associated with cell type-specific functions (Long et al 2016). Given their tissue-restricted expression, lineage-determining transcription factors represent candidates for imposition of cell type-specific responses to DNA damage. In vivo (Goodall et al 2008) or in 3D culture (Thurber et al 2011), MITF and BRN2 are expressed in distinct subpopulations of melanoma cells, likely reflecting a feedback loop in which MITF activates miR-211 expression that represses BRN2 to alleviate the suppression of MITF
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