METTL14 facilitates global genome repair and suppresses skin tumorigenesis

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.

AT Homopolymer Strings as a Motif for Self-Recognition and Repair of Genomes in Salmonella enterica Subspecies I

Adenine and thymine homopolymer strings of at least 8 nucleotides (AT 8+mers) were charac-terized in Salmonella enterica subspecies I and other Eubacteria. Incidence of the motif differed between Eubacteria but not between Salmonella enterica serotypes. Of 481 AT 8+mers loci in serovars Typhimurium, Enteritidis, and Gallinarum, 35 (12.3%) had mutations. We propose that the AT 8+mer motif identifies genomes with optimal gene content and provides self-recognition that facilitates efficient genome repair. A theory that genome regeneration accounts for both serovar diversity and persistence of predominant Salmonella serovars associated provides a new framework for investigating root causes of foodborne illness.

Origin of DNA Repair in the RNA World

The early history of life on Earth likely included a stage in which life existed as self-replicating protocells with single-stranded RNA (ssRNA) genomes. In this RNA world, genome damage from a variety of sources (spontaneous hydrolysis, UV, etc.) would have been a problem for survival. Selection pressure for dealing with genome damage would have led to adaptive strategies for mitigating the damage. In today’s world, RNA viruses with ssRNA genomes are common, and these viruses similarly need to cope with genome damage. Thus ssRNA viruses can serve as models for understanding the early evolution of genome repair. As the ssRNA protocells in the early RNA world evolved, the RNA genome likely gave rise, through a series of evolutionary stages, to the double-stranded DNA (dsDNA) genome. In ssRNA to dsDNA evolution, genome repair processes also likely evolved to accommodate this transition. Some of the basic features of ssRNA genome repair appear to have been retained in descendants with dsDNA genomes. In particular, a type of strand-switching recombination occurs when ssRNA replication is blocked by a damage in the template strand. Elements of this process appear to have a central role in recombinational repair processes during meiosis and mitosis of descendant dsDNA organisms.

A bacterial resolvase first exploits, then constrains intrinsic dynamics of the Holliday junction to direct recombination

Homologous recombination forms and resolves an entangled DNA Holliday Junction (HJ) critical for achieving genome repair. We use single-molecule observation and cluster analysis to probe how prototypic bacterial resolvase RuvC selects two of four possible HJ strands for cleavage. RuvC first exploits, then constrains intrinsic HJ isomer exchange and branch migration dynamics to direct cleavage toward only a desired, catalytically competent HJ conformation, thus controlling recombination products.