In yeast, Sir2 family proteins (sirtuins) regulate gene silencing, recombination, DNA repair, and aging via histone deacetylation. Most of the seven mammalian sirtuins (Sirt1-Sirt7) have been implicated as NAD + -dependent protein deacetylases with targets ranging from transcriptional regulators to metabolic enzymes. We report that neural-specific deletion of sirtuin 6 (Sirt6) in mice leads to postnatal growth retardation due to somatotropic attenuation through low growth hormone (GH) and insulin-like growth factor 1 (IGF1) levels. However, unlike Sirt6 null mice, neural Sirt6-deleted mice do not die from hypoglycemia. Instead, over time, neural Sirt6-deleted mice reach normal size and ultimately become obese. Molecularly, Sirt6 deletion results in striking hyperacetylation of histone H3 lysine 9 (H3K9) and lysine 56 (H3K56), two chromatin marks implicated in the regulation of gene activity and chromatin structure, in various brain regions including those involved in neuroendocrine regulation. On the basis of these findings, we propose that Sirt6 functions as a central regulator of somatic growth and plays an important role in preventing obesity by modulating neural chromatin structure and gene activity.
Classical nonhomologous DNA end-joining (C-NHEJ), which is a major DNA double-strand break (DSB) repair pathway in mammalian cells, plays a dominant role in joining DSBs during Ig heavy chain (IgH) class switch recombination (CSR) in activated B lymphocytes. However, in B cells deficient for one or more requisite C-NHEJ factors, such as DNA ligase 4 (Lig4) or XRCC4, end-joining during CSR occurs by a distinct alternative end-joining (A-EJ) pathway. A-EJ also has been implicated in joining DSBs found in oncogenic chromosomal translocations. DNA ligase 3 (Lig3) and its cofactor XRCC1 are widely considered to be requisite A-EJ factors, based on biochemical studies or extrachromosomal substrate end-joining studies. However, potential roles for these factors in A-EJ of endogenous chromosomal DSBs have not been tested. Here, we report that
Xrcc1
inactivation via conditional gene-targeted deletion in WT or XRCC4-deficient primary B cells does not have an impact on either CSR or
IgH/c-myc
translocations in activated B lymphocytes. Indeed, homozygous deletion of
Xrcc1
does not impair A-EJ of I-SceI–induced DSBs in XRCC4-deficient pro–B-cell lines. Correspondingly, substantial depletion of Lig3 in Lig4-deficient primary B cells or B-cell lines does not impair A-EJ of CSR-mediated DSBs or formation of
IgH/c-myc
translocations. Our findings firmly demonstrate that XRCC1 is not a requisite factor for A-EJ of chromosomal DSBs and raise the possibility that DNA ligase 1 (Lig1) may contribute more to A-EJ than previously considered.
DNAs are one of the most fundamental molecules for life. Quantification of specific sequences is of great importance for biological research and clinical diagnosis. In order to determine extremely low abundant DNAs, we herein develop a novel electrochemical genosensor taking advantage of a smart bipedal DNA walking machine. Magnetic nanomaterials are first employed to enrich target DNA. Strand displacement amplification initiated by target DNA is then designed on the surface of the nanomaterials, the products of which can be used to trigger bipedal DNA walking on the surface of an electrode. Benefiting from triple amplification, ultrahigh sensitivity is achieved for electrochemical analysis of DNA. More importantly, the proposed strategy opens a new avenue for employing the bipedal DNA walker for sensitive detection of various biomolecules with signal amplification.
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