PT  - JOURNAL ARTICLE
AU  - Andrew S. McNeal
AU  - Rachel L. Belote
AU  - Hanlin Zeng
AU  - Marcus Urquijo
AU  - Kendra Barker
AU  - Rodrigo Torres
AU  - Meghan Curtin
AU  - A. Hunter Shain
AU  - Robert H. I. Andtbacka
AU  - Sheri L. Holmen
AU  - David H. Lum
AU  - Timothy H. McCalmont
AU  - Matthew W. VanBrocklin
AU  - Douglas Grossman
AU  - Maria L. Wei
AU  - Ursula E. Lang
AU  - Robert L. Judson-Torres
TI  - BRAF<sup>V600E</sup> induces reversible mitotic arrest in human melanocytes via microRNA-mediated suppression of AURKB
AID  - 10.1101/2020.05.21.109397
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2020.05.21.109397
4099  - http://biorxiv.org/content/early/2021/09/19/2020.05.21.109397.short
4100  - http://biorxiv.org/content/early/2021/09/19/2020.05.21.109397.full
AB  - Benign melanocytic nevi frequently emerge when an acquired BRAFV600E mutation triggers unchecked proliferation and subsequent arrest in melanocytes. Recent observations have challenged the role of oncogene-induced senescence in melanocytic nevus formation, necessitating investigations into alternative mechanisms for the establishment and maintenance of proliferation arrest in nevi. We compared the transcriptomes of melanocytes from healthy human skin, nevi, and melanomas arisen from nevi and identified a set of microRNAs as highly expressed nevus-enriched transcripts. Two of these microRNAs – MIR211-5p and MIR328-3p – induced mitotic failure, genome duplication and proliferation arrest in human melanocytes through convergent targeting of AURKB. We demonstrate that BRAFV600E induces a similar proliferation arrest in primary human melanocytes that is both reversible and conditional. Specifically, BRAFV600E expression stimulates either arrest or proliferation depending on the differentiation state of the melanocyte. We report genome duplication in human melanocytic nevi, reciprocal expression of AURKB and microRNAs in nevi and melanomas, and rescue of arrested human nevus cells with AURKB expression. Together, our data describe an alternative molecular mechanism for melanocytic nevus formation that is congruent with both experimental and clinical observations.Competing Interest StatementRLJ and MLW are inventors on international patent application no. PCT/US2019/023834 concerning the use of microRNAs investigated in this article as molecular diagnostics for melanoma.