| 1. |
- Michel, M., et al.
(författare)
-
Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function
- 2022
-
Ingår i: Science. - Stockholm : American Association for the Advancement of Science. - 0036-8075 .- 1095-9203. ; 376:6600, s. 1471-1476
-
Tidskriftsartikel (refereegranskat)abstract
- Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease 1 (APE1) and initiating repair. Here, we describe a small molecule (TH10785) that interacts with the phenylalanine-319 and glycine-42 amino acids of OGG1, increases the enzyme activity 10-fold, and generates a previously undescribed b,d-lyase enzymatic function. TH10785 controls the catalytic activity mediated by a nitrogen base within its molecular structure. In cells, TH10785 increases OGG1 recruitment to and repair of oxidative DNA damage. This alters the repair process, which no longer requires APE1 but instead is dependent on polynucleotide kinase phosphatase (PNKP1) activity. The increased repair of oxidative DNA lesions with a small molecule may have therapeutic applications in various diseases and aging. © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
|
|
| 2. |
- Gupta, Alok C., et al.
(författare)
-
Multiband optical variability of the blazar OJ 287 during its outbursts in 2015-2016
- 2017
-
Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 465:4, s. 4423-4433
-
Tidskriftsartikel (refereegranskat)abstract
- We present recent optical photometric observations of the blazar OJ 287 taken during 2015 September-2016 May. Our intense observations of the blazar started in 2015 November and continued until 2016 May and included detection of the large optical outburst in 2015 December that was predicted using the binary black hole model for OJ 287. For our observing campaign, we used a total of nine ground-based optical telescopes of which one is in Japan, one is in India, three are in Bulgaria, one is in Serbia, one is in Georgia, and two are in the USA. These observations were carried out in 102 nights with a total of similar to 1000 image frames in BVRI bands, though the majority were in the R band. We detected a second comparably strong flare in 2016 March. In addition, we investigated multiband flux variations, colour variations, and spectral changes in the blazar on diverse time-scales as they are useful in understanding the emission mechanisms. We briefly discuss the possible physical mechanisms most likely responsible for the observed flux, colour, and spectral variability.
|
|
| 3. |
- Berglund, U. W., et al.
(författare)
-
Validation and development of MTH1 inhibitors for treatment of cancer
- 2016
-
Ingår i: Annals of Oncology. - : Elsevier BV. - 0923-7534 .- 1569-8041. ; 27:12, s. 2275-2283
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Previously, we showed cancer cells rely on the MTH1 protein to prevent incorporation of otherwise deadly oxidised nucleotides into DNA and we developed MTH1 inhibitors which selectively kill cancer cells. Recently, several new and potent inhibitors of MTH1 were demonstrated to be non-toxic to cancer cells, challenging the utility of MTH1 inhibition as a target for cancer treatment. Material and methods: Human cancer cell lines were exposed in vitro to MTH1 inhibitors or depleted of MTH1 by siRNA or shRNA. 8-oxodG was measured by immunostaining and modified comet assay. Thermal Proteome profiling, proteomics, cellular thermal shift assays, kinase and CEREP panel were used for target engagement, mode of action and selectivity investigations of MTH1 inhibitors. Effect of MTH1 inhibition on tumour growth was explored in BRAF V600E-mutated malignant melanoma patient derived xenograft and human colon cancer SW480 and HCT116 xenograft models. Results: Here, we demonstrate that recently described MTH1 inhibitors, which fail to kill cancer cells, also fail to introduce the toxic oxidized nucleotides into DNA. We also describe a new MTH1 inhibitor TH1579, (Karonudib), an analogue of TH588, which is a potent, selective MTH1 inhibitor with good oral availability and demonstrates excellent pharmacokinetic and anti-cancer properties in vivo. Conclusion: We demonstrate that in order to kill cancer cells MTH1 inhibitors must also introduce oxidized nucleotides into DNA. Furthermore, we describe TH1579 as a best-in-class MTH1 inhibitor, which we expect to be useful in order to further validate the MTH1 inhibitor concept.
|
|
| 4. |
- Gad, Helge, et al.
(författare)
-
MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
-
Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
-
Tidskriftsartikel (refereegranskat)abstract
- Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
|
|
| 5. |
- Dhiman, Vinit, et al.
(författare)
-
Multiband optical variability of the TeV blazar PG 1553+113 in 2019
- 2022
-
Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 519:2, s. 2796-2811
-
Tidskriftsartikel (refereegranskat)abstract
- We report the flux and spectral variability of PG 1553 + 113 on intra-night (IDV) to short-term time-scales using BVRI data collected over 91 nights from 28 February to 8 November 2019 employing 10 optical telescopes: three in Bulgaria, two each in India and Serbia, and one each in Greece, Georgia, and Latvia. We monitored the blazar quasi-simultaneously for 16 nights in the V and R bands and 8 nights in the V, R, I bands and examined the light curves (LCs) for intra-day flux and colour variations using two powerful tests: the power-enhanced F-test and the nested ANOVA test. The source was found to be significantly (>99 per cent) variable in 4 nights out of 27 in R-band, 1 out of 16 in V-band, and 1 out of 6 nights in I-band. No temporal variations in the colours were observed on IDV time-scale. During the course of these observations the total variation in R-band was 0.89 mag observed. We also investigated the spectral energy distribution (SED) using B-, V-, R-, and I-band data. We found optical spectral indices in the range of 0.878 +/- 0.029 to 1.106 +/- 0.065 by fitting a power law (F-nu proportional to nu(-alpha)) to these SEDs of PG 1553 + 113. We found that the source follows a bluer-when-brighter trend on IDV time-scales. We discuss possible physical causes of the observed spectral variability.
|
|
| 6. |
|
|
| 7. |
|
|
