By studying the genomes of a large group of people who have lived to 100 years and older, a group led by scientists from the Albert Einstein College of Medicine have uncovered rare genetic coding variants linked with longevity and protection against age-related diseases. In the study, which appears in Nature Aging this week, the investigators performed whole-exome sequencing in a cohort of 515 Ashkenazi Jewish centenarians, looking for enriched rare coding variants. They find that most longevity-associated variants converge upon conserved insulin/insulin-like growth factor 1 signaling and AMP-activating protein kinase signaling pathways. They also find that the centenarians have certain pathogenic rare coding variants similar to a control group of Ashkenazi Jews, suggesting that rare variants detected in the conserved longevity pathways are protective against age-related pathology. "The genetic component of extreme human longevity constitutes, at least in part, rare coding variants in pathways that protect against aging, including those that control longevity in model organisms," the authors write. GenomeWeb has more on this, here.
The structural basis for transcription-coupled DNA repair (TCR) in human cells is presented in Nature this week, providing new insights into the molecular mechanism underlying this process. TCR is used by eukaryotic cells to remove bulky DNA lesions from the genome and protect cells against ultraviolet irradiation. It begins when RNA polymerase II (Pol II) stalls at a DNA lesion and recruits the Cockayne syndrome protein CSB, the E3 ubiquitin ligase, CRL4CSA, and UV-stimulated scaffold protein A (UVSSA). In the study, scientists from the Max Planck Institute for Biophysical Chemistry used cryo-electron microscopy to resolve five different Pol II elongation complex structures containing CSB, the CSA-DDB1 complex or the complete CRL4CSA, and UVSSA. Combined with published data, these structures provide a model for TCR.