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Title: METTL14 facilitates global genome repair and suppresses skin tumorigenesis.

Authors: Yang, Zizhao; Yang, Seungwon; Cui, Yan-Hong; Wei, Jiangbo; Shah, Palak; Park, Gayoung; Cui, Xiaolong; He, Chuan; He, Yu-Ying

Published In Proc Natl Acad Sci U S A, (2021 08 31)

Abstract: Global genome repair (GGR), a subpathway of nucleotide excision repair, corrects bulky helix-distorting DNA lesions across the whole genome and is essential for preventing mutagenesis and skin cancer. Here, we show that METTL14 (methyltransferase-like 14), a critical component of the N6-methyladenosine (m6A) RNA methyltransferase complex, promotes GGR through regulating m6A mRNA methylation-mediated DDB2 translation and suppresses ultraviolet B (UVB) radiation-induced skin tumorigenesis. UVB irradiation down-regulates METTL14 protein through NBR1-dependent selective autophagy. METTL14 knockdown decreases GGR and DDB2 abundance. Conversely, overexpression of wild-type METTL14 but not its enzymatically inactive mutant increases GGR and DDB2 abundance. METTL14 knockdown decreases m6A methylation and translation of the DDB2 transcripts. Adding DDB2 reverses the GGR repair defect in METTL14 knockdown cells, indicating that METTL14 facilitates GGR through regulating DDB2 m6A methylation and translation. Similarly, knockdown of YTHDF1, an m6A reader promoting translation of m6A-modified transcripts, decreases DDB2 protein levels. Both METTL14 and YTHDF1 bind to the DDB2 transcript. In mice, skin-specific heterozygous METTL14 deletion increases UVB-induced skin tumorigenesis. Furthermore, METTL14 as well as DDB2 is down-regulated in human and mouse skin tumors and by chronic UVB irradiation in mouse skin, and METTL14 level is associated with the DDB2 level, suggesting a tumor-suppressive role of METTL14 in UVB-associated skin tumorigenesis in association with DDB2 regulation. Taken together, these findings demonstrate that METTL14 is a target for selective autophagy and acts as a critical epitranscriptomic mechanism to regulate GGR and suppress UVB-induced skin tumorigenesis.

PubMed ID: 34452996 Exiting the NIEHS site

MeSH Terms: Animals; Autophagy; Carcinogenesis/genetics*; Cell Line, Tumor; DNA Damage; DNA Repair/genetics; DNA Repair/physiology*; DNA-Binding Proteins/metabolism; Female; Genes, Tumor Suppressor/radiation effects; Humans; Intracellular Signaling Peptides and Proteins/metabolism; Male; Membrane Glycoproteins/metabolism; Methylation; Methyltransferases/genetics; Methyltransferases/physiology*; Mice; Nerve Tissue Proteins/metabolism; RNA, Messenger/metabolism; RNA-Binding Proteins/metabolism; Skin Neoplasms/etiology; Skin Neoplasms/genetics*; Ultraviolet Rays

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