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This Week in PNAS: Feb 16, 2016

In the Proceedings of the National Academy of Sciences this week, researchers from the UK, Netherlands, and Italy present findings from a deep phenotyping analysis of individuals with a rare DNA repair disorder called xeroderma pigmentosum, which makes individuals especially susceptible to sunburns, pigmentation, skin cancer, and other conditions caused by ultraviolet light exposure. The team focused on 89 individuals with xeroderma pigmentosum, looking at how clinical features and phenotypes coincided with mutations in eight DNA damage genes. For example, the study's authors saw particularly elevated skin cancer risk in individuals from three xeroderma pigmentosum sub-groups with relatively mild sunburn reactions, while other mutations made patients more prone to eye damage or neurological symptoms. "Our findings provide new insights into the mechanisms of carcinogenesis, ocular surface disease, and neurodegeneration," they write, "as well as providing improved clinical management and more definitive prognostic predictions."

A Hungarian team describes an improved version of multiplex automated genome engineering that it developed to assess mutational consequences in bacteria. The approach, called pORTMAGE, relies on a set of plasmids that produce methyl directed mismatch repair (MMR) system mutants under specific temperature conditions, making it possible to sneak in and integrate new sequences while DNA repair is temporarily impaired. Though the researchers' proof-of-principle pORTMAGE experiments were done in Escherichia coli, the approach is expected to prove useful in other bacterial species with conserved MMR features. "Because our protocol allows for rapid switching between mutator and non-mutator states, it minimizes the time the bacterial population spends susceptible to the accumulation of off-target mutations," they note, adding that the pORTMAGE method "simultaneously allows genome editing and mutant library generation in several biotechnologically and clinically relevant bacterial species."

Finally, an international team led by investigators at the University of Texas MD Anderson Cancer Center explores the role that PREX2 gene mutations play in the development of melanoma. Following up on findings from previous cancer studies that implicated PREX2 mutations in cutaneous melanoma and pancreatic ductal adenocarcinoma, the researchers developed a transgenic mouse model with inducible truncating mutations in PREX2, a gene that typically codes for a protein that binds the tumor suppressor PTEN, before crossing them with a mouse model of melanoma with NRAS mutations. Together with a comparative gene expression analysis, the transgenic mouse experiments hint that PREX2 truncations speed up melanoma development when NRAS mutations are present due to downstream effects on cell cycle regulators.