The protective role of DOT1L in UV-induced melanomagenesis

Bo Zhu,Christine G Lian,Changpeng Han,Colin R Goding,Wenyi Wei,Jay L Hess ,Xiang Chen,Yujiang Geno Shi ,Tao Wang,Lixin Wan,Jie Zhang,Shuyang Chen,Min Liu,Jingxuan Pan,Jun Zhou,Chengqian Yin,Xiaoyang Zhang,Cong Peng,Dali Liu,Zhi Xu ,Sharon Prince,Peilin Ma,Yongjun Wang,Hongshen Wang,Zhi Wei,Zhenyu Xuan,Nicholas K Hayward,Zhao‐Qian Liu ,Xiumei Gao,Rutao Cui

doi:10.1038/s41467-017-02687-7

Abstract

The DOT1L histone H3 lysine 79 (H3K79) methyltransferase plays an oncogenic role in MLL-rearranged leukemogenesis. Here, we demonstrate that, in contrast to MLL-rearranged leukemia, DOT1L plays a protective role in ultraviolet radiation (UVR)-induced melanoma development. Specifically, the DOT1L gene is located in a frequently deleted region and undergoes somatic mutation in human melanoma. Specific mutations functionally compromise DOT1L methyltransferase enzyme activity leading to reduced H3K79 methylation. Importantly, in the absence of DOT1L, UVR-induced DNA damage is inefficiently repaired, so that DOT1L loss promotes melanoma development in mice after exposure to UVR. Mechanistically, DOT1L facilitates DNA damage repair, with DOT1L-methylated H3K79 involvement in binding and recruiting XPC to the DNA damage site for nucleotide excision repair (NER). This study indicates that DOT1L plays a protective role in UVR-induced melanomagenesis.

Highlights

The DOT1L histone H3 lysine 79 (H3K79) methyltransferase plays an oncogenic role in MLLrearranged leukemogenesis
DOT1L has a well-established role in which it frequently interacts with mixed lineage leukemia (MLL) oncogenic fusion proteins, such as AF4, ENL, ELL, and AF1012,13, to induce H3K79 methylation and constitutively activate a leukemic transcriptional program resulting in transformation[14,15]
To explore how DOT1L might function in melanoma development, we analyzed somatic mutation data of melanomas collected from The Cancer Genome Atlas (TCGA) data portal and found 427,383 somatic variant calls made from 470 human samples spanning 19,563 distinct genes

Summary

Introduction

The DOT1L histone H3 lysine 79 (H3K79) methyltransferase plays an oncogenic role in MLLrearranged leukemogenesis. We demonstrate that, in contrast to MLL-rearranged leukemia, DOT1L plays a protective role in ultraviolet radiation (UVR)-induced melanoma development. After the initial recognition step, repair proteins, such as XPA, and TFIIH complex including the essential subunit p62, bind to the damage site, which promotes recruitment of other NER factors This allows incision of the damaged strand by repair endonucleases, including ERCC1/XPF and XPG and restoration of the normal nucleotide sequence[11]. DOT1L has a well-established role in which it frequently interacts with mixed lineage leukemia (MLL) oncogenic fusion proteins, such as AF4, ENL, ELL, and AF1012,13, to induce H3K79 methylation and constitutively activate a leukemic transcriptional program resulting in transformation[14,15]. In the absence of DOT1L, UVR-induced DNA damage is inefficiently repaired such that DOT1L loss promotes melanoma development in mice after exposure to UVR

Methods

Results

Conclusion