Shortcomings of ethnicity-based carrier screening for conditions associated with Ashkenazi Jewish ancestry.

Purpose: Carrier screening identifies reproductive risk for autosomal recessive and X-linked genetic conditions. Currently, some medical society guidelines continue to recommend ethnicity-based carrier screening for conditions associated with Ashkenazi Jewish (AJ) ancestry. We assessed the utility and limitations of these guidelines in a large, ethnically and genetically diverse cohort of genotyped individuals.

Identifying Ashkenazi Jewish BRCA1/2 founder variants in individuals who do not self-report Jewish ancestry.

Current guidelines recommend BRCA1 and BRCA2 genetic testing for individuals with a personal or family history of certain cancers. Three BRCA1/2 founder variants - 185delAG (c.68_69delAG), 5382insC (c.

SIRT6 deacetylates H3K18ac at pericentric chromatin to prevent mitotic errors and cellular senescence.

Pericentric heterochromatin silencing at mammalian centromeres is essential for mitotic fidelity and genomic stability. Defective pericentric silencing has been observed in senescent cells, aging tissues, and mammalian tumors, but the underlying mechanisms and functional consequences of these defects are unclear. Here, we uncover an essential role of the human SIRT6 enzyme in pericentric transcriptional silencing, and we show that this function protects against mitotic defects, genomic instability, and cellular senescence.

Cell-cycle and DNA damage regulation of the DNA mismatch repair protein Msh2 occurs at the transcriptional and post-transcriptional level.

DNA mismatch repair during replication is a conserved process essential for maintaining genomic stability. Mismatch repair is also implicated in cell-cycle arrest and apoptosis after DNA damage. Because yeast and human mismatch repair systems are well conserved, we have employed the budding yeast Saccharomyces cerevisiae to understand the regulation and function of the mismatch repair gene MSH2.

SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation.

Sirtuin proteins regulate diverse cellular pathways that influence genomic stability, metabolism and ageing. SIRT7 is a mammalian sirtuin whose biochemical activity, molecular targets and physiological functions have been unclear. Here we show that SIRT7 is an NAD(+)-dependent H3K18Ac (acetylated lysine 18 of histone H3) deacetylase that stabilizes the transformed state of cancer cells.

Finding a target for resveratrol.

Despite resveratrol's well-documented health benefits, its mechanism of action remains controversial. In particular, the direct molecular target of resveratrol has been elusive. Park et al.

SIRT6 is required for maintenance of telomere position effect in human cells.

In Saccharomyces cerevisiae, the repressive chromatin environment at telomeres gives rise to telomere position effect (TPE), the epigenetic silencing of telomere-proximal genes. Chromatin-modifying factors that control TPE in yeast have been extensively studied, and, among these, the lifespan regulator and silencing protein Sir2 has a pivotal role. In contrast, the factors that generate and maintain silent telomeric chromatin in human cells remain largely unknown.

Lysine methylation of the NF-κB subunit RelA by SETD6 couples activity of the histone methyltransferase GLP at chromatin to tonic repression of NF-κB signaling.

Signaling via the methylation of lysine residues in proteins has been linked to diverse biological and disease processes, yet the catalytic activity and substrate specificity of many human protein lysine methyltransferases (PKMTs) are unknown. We screened over 40 candidate PKMTs and identified SETD6 as a methyltransferase that monomethylated chromatin-associated transcription factor NF-κB subunit RelA at Lys310 (RelAK310me1). SETD6-mediated methylation rendered RelA inert and attenuated RelA-driven transcriptional programs, including inflammatory responses in primary immune cells.

Chromatin regulation and genome maintenance by mammalian SIRT6.

Saccharomyces cerevisiae Sir2 is an NAD(+)-dependent histone deacetylase that links chromatin silencing to genomic stability, cellular metabolism and lifespan regulation. In mice, deficiency for the Sir2 family member SIRT6 leads to genomic instability, metabolic defects and degenerative pathologies associated with aging. Until recently, SIRT6 was an orphan enzyme whose catalytic activity and substrates were unclear.

Functional dissection of SIRT6: identification of domains that regulate histone deacetylase activity and chromatin localization.

The mammalian sirtuin SIRT6 is a site-specific histone deacetylase that regulates chromatin structure. SIRT6 is implicated in fundamental biological processes in aging, including maintaining telomere integrity, fine-tuning aging-associated gene expression programs, preventing genomic instability, and maintaining metabolic homeostasis. Despite these important functions, the basic molecular determinants of SIRT6 enzymatic function--including the mechanistic and regulatory roles of specific domains of SIRT6--are not well understood.

Conditional telomerase induction causes proliferation of hair follicle stem cells.

TERT, the protein component of telomerase, serves to maintain telomere function through the de novo addition of telomere repeats to chromosome ends, and is reactivated in 90% of human cancers. In normal tissues, TERT is expressed in stem cells and in progenitor cells, but its role in these compartments is not fully understood. Here we show that conditional transgenic induction of TERT in mouse skin epithelium causes a rapid transition from telogen (the resting phase of the hair follicle cycle) to anagen (the active phase), thereby facilitating robust hair growth.