global genome repair
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2021 ◽  
Vol 118 (35) ◽  
pp. e2025948118
Author(s):  
Zizhao Yang ◽  
Seungwon Yang ◽  
Yan-Hong Cui ◽  
Jiangbo Wei ◽  
Palak Shah ◽  
...  

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.


2021 ◽  
Vol 22 (2) ◽  
pp. 952
Author(s):  
Thanyalak Kraithong ◽  
Silas Hartley ◽  
David Jeruzalmi ◽  
Danaya Pakotiprapha

Double stranded DNA (dsDNA), the repository of genetic information in bacteria, archaea and eukaryotes, exhibits a surprising instability in the intracellular environment; this fragility is exacerbated by exogenous agents, such as ultraviolet radiation. To protect themselves against the severe consequences of DNA damage, cells have evolved at least six distinct DNA repair pathways. Here, we review recent key findings of studies aimed at understanding one of these pathways: bacterial nucleotide excision repair (NER). This pathway operates in two modes: a global genome repair (GGR) pathway and a pathway that closely interfaces with transcription by RNA polymerase called transcription-coupled repair (TCR). Below, we discuss the architecture of key proteins in bacterial NER and recent biochemical, structural and single-molecule studies that shed light on the lesion recognition steps of both the GGR and the TCR sub-pathways. Although a great deal has been learned about both of these sub-pathways, several important questions, including damage discrimination, roles of ATP and the orchestration of protein binding and conformation switching, remain to be addressed.


Oncotarget ◽  
2016 ◽  
Vol 7 (38) ◽  
pp. 60940-60953 ◽  
Author(s):  
Timothy Budden ◽  
Ryan J. Davey ◽  
Ricardo E. Vilain ◽  
Katie A. Ashton ◽  
Stephen G. Braye ◽  
...  

PLoS ONE ◽  
2013 ◽  
Vol 8 (8) ◽  
pp. e70424 ◽  
Author(s):  
Nikola A. Bowden ◽  
Katie A. Ashton ◽  
Ricardo E. Vilain ◽  
Kelly A. Avery-Kiejda ◽  
Ryan J. Davey ◽  
...  

PLoS Genetics ◽  
2010 ◽  
Vol 6 (5) ◽  
pp. e1000941 ◽  
Author(s):  
Hannes Lans ◽  
Jurgen A. Marteijn ◽  
Björn Schumacher ◽  
Jan H. J. Hoeijmakers ◽  
Gert Jansen ◽  
...  

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