In this study we find that the function of BRCA1 inhibits the microtubule nucleation function of centrosomes. In particular, cells in early S phase have quiescent centrosomes due to BRCA1 activity, which inhibits the association of ␥-tubulin with centrosomes. We find that modification of either of two specific lysine residues (Lys-48 and Lys-344) of ␥-tubulin, a known substrate for BRCA1-dependent ubiquitination activity, led to centrosome hyperactivity. Interestingly, mutation of ␥-tubulin lysine 344 had a minimal effect on centrosome number but a profound effect on microtubule nucleation function, indicating that the processes regulating centrosome duplication and microtubule nucleation are distinct. Using an in vitro aster formation assay, we found that BRCA1-dependent ubiquitination activity directly inhibits microtubule nucleation by centrosomes. Mutant BRCA1 protein that was inactive as a ubiquitin ligase did not inhibit aster formation by the centrosome. Further, a BRCA1 carboxy-terminal truncation mutant that was an active ubiquitin ligase lacked domains critical for the inhibition of centrosome function. These experiments reveal an important new functional assay regulated by the BRCA1-dependent ubiquitin ligase, and the results suggest that the loss of this BRCA1 activity could cause the centrosome hypertrophy and subsequent aneuploidy typically found in breast cancers.BRCA1 is a breast-and ovary-specific tumor suppressor, and mutations in this gene have been found in approximately 40% of familial breast cancer cases and most of combined familial breast and ovarian cancers (1,8,43). BRCA1 is a large phosphoprotein consisting of 1,863 amino acids in humans, with a number of domains that interact directly or indirectly with many proteins with diverse functions such as transcription control, cell cycle regulation, chromatin remodeling, and DNA repair (30,40). BRCA1 has a RING domain at its amino terminus, and in association with BARD1, the heterodimer is an E3 ubiquitin ligase (16,46). Identifying the critical role for the BRCA1-dependent ubiquitin ligase activity in breast cell biology has been a major focus of research. In this study, we find that the BRCA1-associated E3 ubiquitin ligase directly regulates centrosome function.Centrosomes are the major microtubule (MT)-organizing centers of animal cells. Centrosomes control the number, polarity, and distribution of MTs, which are important in regulating cell polarity, shape, motility, intracellular transport, and cell division (13). In a normal cell, centrosomes start duplicating at early-S phase, and by M phase the cell has two mature centrosomes that form the bipolar spindle and ensure proper segregation of chromosomes to the two daughter cells. Currently more than 150 proteins have been shown to localize to centrosomes (3).The cells in many tumor types, including breast cancer, display numerical and structural centrosome aberrations, which have been collectively termed centrosomal hypertrophy. Structural abnormalities include increased centrosomal volu...

The magnitude of association between thyroid cancer screening in South Korea and the incidence of thyroid cancer strongly suggests that screening is the most important driver of the epidemic of thyroid cancer, particularly among females. Thyroid cancer screening, however, was only associated with the increase of one tumor histology, papillary thyroid cancer, and it did not have any association with thyroid cancer mortality. The extent to which opportunistic thyroid cancer screening is converting thousands of asymptomatic persons to cancer patients without any known benefit to them needs to be examined carefully.

Eco-friendly green Zn-Ag-In-S (ZAIS) and red Zn-Cu-In-S (ZCIS) core/shell-like alloyed quantum dots (QDs) have been synthesized by a facile hot-injection method with a multiple injection approach. Broad full-width at half-maximum (fwhm) of the photoluminescence (PL) emission and tunability of the green ZAIS and red ZCIS QDs were obtained by adopting a low-temperature core growth and high-temperature multiple alloyed reaction. The alloyed green ZAIS and red ZCIS QDs reached PL quantum yields as high as 0.61 and 0.53; fwhm of the PL peaks were as wide as 81 and 106 nm, respectively. This demonstrates the practical realization of white down-converted light-emitting diodes (DC-LEDs), fully covering the whole visible wavelength range and the cyan gap, using two broad fwhm green ZAIS and red ZCIS QDs. We also characterized the vision and color performance using luminous efficacy (LE), color rendering index (CRI), special CRI for strong red (R9), and color quality scale (CQS) of white DC-LEDs incorporated with green ZAIS and red ZCIS QDs at the correlated color temperature (CCT) range of 2700-10 000 K. The tricolor white DC-LED using broad fwhm green-emitting ZAIS and red-emitting ZCIS core/shell-like alloyed QDs exhibits a moderate LE (31.2 lm/W) and ultrahigh color qualities (CRI = 97, R9 = 97, and CQS = 94) with warm white at a CCT of 3500 K.

Highly efficient bright green‐emitting ZnAgInS (ZAIS)/ZnInS (ZIS)/ZnS alloy core/inner‐shell/shell quantum dots (QDs) are synthesized using a multistep hot injection method with a highly concentrated zinc acetate dihydrate precursor. ZAIS/ZIS/ZnS QD growth is realized via five sequential steps: a core growth process, a two‐step alloying–shelling process, and a two‐step shelling process. To enhance the photoluminescence quantum yield (PLQY), a ZIS inner‐shell is synthesized and added with a band gap located between the ZAIS alloy‐core and ZnS shell using a strong exothermic reaction. The synthesized ZAIS/ZIS/ZnS QDs shows a high PLQY of 87% with peak wavelength of 501 nm. Tripackage white down‐converted light‐emitting diodes (DC‐LEDs) are realized using an InGaN blue (B) LED, a green (G) ZAIS/ZIS/ZS QD‐based DC‐LED, and a red (R) ZnCuInS/ZnS QD‐based DC‐LED with correlated color temperature from 2700 to 10 000 K. The red, green, and blue tripackage white DC‐LEDs exhibit high luminous efficacy of 72 lm W−1 and excellent color qualities (color rendering index (CRI, Ra) = 95 and the special CRI for red (R9) = 93) at 2700 K.

TopBP1 plays important roles in chromosome replication, DNA damage response, and other cellular regulatory functions in vertebrates. Although the roles of TopBP1 have been studied mostly in cancer cell lines, its physiological function remains unclear in mice and untransformed cells. We generated conditional knock-out mice in which exons 5 and 6 of the TopBP1 gene are flanked by loxP sequences. Although TopBP1-deficient embryos developed to the blastocyst stage, no homozygous mutant embryos were recovered at E8.5 or beyond, and completely resorbed embryos were frequent at E7.5, indicating that mutant embryos tend to die at the periimplantation stage. This finding indicated that TopBP1 is essential for cell proliferation during early embryogenesis. Ablation of TopBP1 in TopBP1 flox/flox mouse embryonic fibroblasts and 3T3 cells using Cre recombinase-expressing retrovirus arrests cell cycle progression at the G 1 , S, and G 2 /M phases. The TopBP1-ablated mouse cells exhibit phosphorylation of H2AX and Chk2, indicating that the cells contain DNA breaks. The TopBP1-ablated mouse cells enter cellular senescence. Although RNA interference-mediated knockdown of TopBP1 induced cellular senescence in human primary cells, it induced apoptosis in cancer cells. Therefore, TopBP1 deficiency in untransformed mouse and human primary cells induces cellular senescence rather than apoptosis. These results indicate that TopBP1 is essential for cell proliferation and maintenance of chromosomal integrity.TopBP1 5 is conserved in eukaryotes and contains repeats of BRCA1 carboxyl-terminal motifs, which are found in proteins involved in DNA repair and regulation of cell cycle checkpoints (1-6). Recent findings indicate that TopBP1 participates in the loading of Cdc45 for the assembly of the preinitiation complex that is necessary for chromosomal DNA replication (7-11). Knockdown of TopBP1 in human cancer cells showed that TopBP1 is necessary for the activation of cyclin E/CDK2 and Cdc7/Dbf4 kinases as well as the loading of DNA polymerase onto chromatin (12). In response to replication fork stalling or DNA damage, TopBP1 functions as an activator of the ATR⅐ATRIP complex by binding to Rad9 of the Rad9⅐Hus1⅐Rad1 complex (13,14). The activated ATR phosphorylates Chk1, Nbs1, Smc1, and H2AX (15-18). TopBP1 also mediates ATR-mediated Chk1 activation by facilitating the interaction of claspin and Chk1 (19,20). Furthermore, association of TopBP1 with NBS1 is involved in double-stranded DNA break-induced homologous recombination repair (21). Therefore, TopBP1 plays crucial roles in the maintenance of genomic integrity.TopBP1 regulates gene expression. Binding of TopBP1 to E2F1 represses E2F1 proapoptotic activity by recruiting the Brg1⅐Brm chromatin remodeling complex (22). TopBP1 also binds to the DNA binding domain of p53 and inhibits the promoter binding activity of this protein (23). Therefore, TopBP1 depletion derepresses the proapoptotic activity of p53 and E2F1 and induces cellular apoptosis. In addition, TopBP1 represses Miz-1 express...