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

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.

LncRNA BCYRN1/miR-490-3p/POU3F2, served as a ceRNA network, is connected with worse survival rate of hepatocellular carcinoma patients and promotes tumor cell growth and metastasis

“…POU3F2, which belongs to the class III POU factors, also called Brn2 or N-Oct3, has been reported to be closely associated with cell proliferation or even elevated the potential for metastasis [22][23][24]. Brn2 was revealed to inhibit apoptosis and reprogram DNA damage repair, and was connected with a high somatic mutation burden in melanoma [36]. It has been observed that POU3F2 conduced to cellular responses against oxaliplatin in human colon cancer cells by regulating tNOX [37].…”

MITF—the first 25 years

“…Although BRN2 can bind elements within the MITF promoter, and can clearly suppress a proapoptotic gene expression program (Herbert et al 2019), it is also possible that it exerts its transcriptional function by cooperating with other sequence-specific transcription factors rather than regulating transcription by itself. Notably, mass spectrometry (MS) analysis of BRN2-associated proteins failed to identify a significant association with non-DNA-binding transcription cofactors.…”

“…Notably, mass spectrometry (MS) analysis of BRN2-associated proteins failed to identify a significant association with non-DNA-binding transcription cofactors. Instead, BRN2 is associated with the DNA-damage-response factors Ku70/Ku80 and PARP1 and plays a role in DNA damage repair by enhancing nonhomologous end-joining at the expense of homologous recombination (Herbert et al 2019). Thus, an ability of BRN2 to exchange cooperating DNAbinding cofactors under different conditions-for example, in vitro versus in vivo-might explain how it could switch from a repressor to an activator of MITF.…”

“…Alternatively, it has also been suggested that BRN2's ability to regulate MITF may reflect heterogeneity in MAPK signaling (Wellbrock and Arozerena 2015). Notably, BRN2's ability to bind DNA appears to be controlled by an intramolecular conformation switch regulated in part by two phosphorylation sites within its N-terminal region that can be modified by p38, a stress-activated kinase downstream from UV and ROS (Herbert et al 2019). Thus, it seems likely that the interplay between stress and MAPK signaling will be important in determining BRN2 function in the regulation of MITF.…”

Report of the 23rd Meeting on Signal Transduction 2019—Trends in Cancer and Infection

“…Melanoma tumours with activating β-catenin mutations exhibit enhanced MiTF and Brn2 expression. Larue shows that Mitf-M affects proliferation, survival and transformation of melanocytes by interfering with cyclin-dependent kinase 2 and 4, p21 and BRN2 [11,12].…”