Molecular and Cellular Biology

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ISSN / EISSN : 0270-7306 / 1098-5549
Published by: American Society for Microbiology (10.1128)
Total articles ≅ 31,534
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Yoo Jin Joo,
Molecular and Cellular Biology;

In our previously published studies, RNA polymerase II transcription initiation complexes were assembled from yeast nuclear extracts onto immobilized transcription templates and analyzed by quantitative mass spectrometry. In addition to the expected basal factors and coactivators, we discovered that the uncharacterized protein Gds1/YOR355W showed activator-stimulated association with promoter DNA. Gds1 co-precipitated with the histone H4 acetyltransferase NuA4, and its levels often tracked with NuA4 in immobilized template experiments. GDS1 deletion led to reduction in H4 acetylation in vivo, and caused other phenotypes consistent with partial loss of NuA4 activity. Genome-wide chromatin immunoprecipitation revealed that the reduction in H4 acetylation was strongest at ribosomal protein gene promoters and other genes with high NuA4 occupancy. Therefore, while Gds1 is not a stoichiometric subunit of NuA4, we propose that it interacts with and modulates NuA4 in specific promoter contexts. Gds1 has no obvious metazoan homolog, but the Alphafold2 algorithm predicts that a section of Gds1 resembles the winged-helix/forkhead domain found in DNA-binding proteins such as the FOX transcription factors and histone H1.
Aiwen Jiang, Hongyun Guo, Liangliang Zhang, Xiaoyu Jiang, Xiying Zhang, Wangjun Wu, Honglin Liu
Molecular and Cellular Biology;

The activity of AMPKα is reduced in type-2 diabetes, and type-2 diabetes is associated with muscular atrophy. To date, there is little known about the mechanism by which FFA participates in muscular impairment. The purpose of the present study was to explore whether FFA damages myogenesis through AMPKα-HDAC4-miR-206 pathway. The results showed that 1mM FFA produced lipid accumulation, significantly impaired insulin signaling pathway and decreased myogenic differentiation of C2C12 myoblast cells. FFA reduced LKB1-AMPKα pathway; activation of AMPKα rescued the myogenic impairment caused by FFA ( P< 0.05). AMPKα promoted myogenesis by regulating the expression of miR-206 through HDAC4 ( P< 0.05); AMPKα affected cell cycle and cell proliferation to promote myogenesis by regulating miR-206 and miR-206’s target gene - cyclin D1. In addition, AICAR and HDAC4 siRNA promoted myogenic differentiation compared with FFA group; however, this positive effect was significantly down-regulated after transfection of miR-206 inhibitor. In summary, AMPKα plays positive roles in myogenic differentiation and myogenesis, and FFA decreased myogenic differentiation and myotubes formation through AMPKα-HDAC4-miR-206 pathway.
Priyanka Barman, Rwik Sen, Amala Kaja, Jannatul Ferdoush, Shalini Guha, Chhabi K. Govind,
Molecular and Cellular Biology;

San1 ubiquitin ligase is involved in nuclear protein quality control via its interaction with intrinsically disordered proteins for ubiquitylation and proteasomal degradation. Since several transcription/chromatin regulatory factors contain intrinsically disordered domains and can be inhibitory to transcription when in excess, San1 might be involved in transcription regulation. To address this, we analyzed the role of San1 in genome-wide association of TBP [that nucleates pre-initiation complex (PIC) formation for transcription initiation] and RNA polymerase II (Pol II). Our results reveal the roles of San1 in regulating TBP recruitment to the promoters and Pol II association with the coding sequences, and hence PIC formation and coordination of elongating Pol II, respectively. Consistently, transcription is altered in the absence of San1. Such transcriptional alteration is associated with impaired ubiquitylation and proteasomal degradation of Spt16 and gene association of Paf1, but not the incorporation of centromeric histone, Cse4, into the active genes in Δsan1 . Collectively, our results demonstrate distinct functions of a nuclear protein quality control factor in regulating the genome-wide PIC formation and elongating Pol II (and hence transcription), thus unraveling new gene regulatory mechanisms.
Sanchita Rauth, Saswati Karmakar, Ashu Shah, Parthasarathy Seshacharyulu, Rama Krishna Nimmakayala, Koelina Ganguly, Rakesh Bhatia, Sakthivel Muniyan, Sushil Kumar, Samikshan Dutta, et al.
Molecular and Cellular Biology;

RNA polymerase II-associated factor 1 (PAF1)/pancreatic differentiation 2 (PD2) is a core subunit of the human PAF1 complex (PAF1C) that regulates the RNA polymerase II function during transcriptional elongation. PAF1/PD2 has also been linked to the oncogenesis of pancreatic ductal adenocarcinoma (PDAC). Here, we report that PAF1/PD2 undergoes post-translational modification (PTM) through SUMOylation, enhancing the radiation resistance of PDAC cells. We identified that PAF1/PD2 is preferentially modified by small ubiquitin-related modifier 1 (SUMO 1), and mutating the residues (K)-150 and 154 by site-directed mutagenesis reduces the SUMOylation. Interestingly, PAF1/PD2 was found to directly interact with the promyelocytic leukemia (PML) protein in response to radiation and inhibiton of PAF1/PD2 SUMOylation at K-150/154 affects its interaction with PML. Our results demonstrate that SUMOylation of PAF1/PD2 increased in the radiated pancreatic cancer cells. Further, inhibition of SUMOylation or PML reduces the cell growth and proliferation of PDAC cells after radiation treatment. These results suggest that SUMOylation of PAF1/PD2 interacts with PTM for PDAC cell survival. Furthermore, abolishing the SUMOylation in PDAC cells enhances the effectiveness of radiotherapy. Overall, our results demonstrate a novel PTM and PAF1/PD2 interaction through SUMOylation and inhibiting the SUMOylation of PAF1/PD2 enhance the therapeutic efficacy for PDAC.
Salar Ahmad, Valérie Côté, Jacques Côté
Molecular and Cellular Biology;

The repair of DNA double-strand breaks (DSBs) occurs in chromatin and several histone post-translational modifications have been implicated in the process. Modifications of histone H2A N-terminal tail has also been linked to DNA damage response, through acetylation or ubiquitination of lysine residues that regulate repair pathway choice. Here, we characterize a new DNA damage-induced phosphorylation on chromatin, at serine 15 of H2A in yeast. We show that this SQ motif functions independently of the classical S129 C-terminal site (γH2A) and mutant mimicking constitutive phosphorylation increases cell sensitivity to DNA damage. H2AS129ph is induced by Tel1 ATM and Mec1 ATR , and loss of Lcd1 ATRIP or Mec1 signaling decreases γH2A spreading distal to the DSB. In contrast, H2AS15ph is completely dependent on Lcd1 ATRIP , indicating that this modification only happens when end resection is engaged. This is supported by an increase of RPA and a decrease in DNA signal near the DSB in the H2AS-15E phosphomimic mutant, indicating higher resection. This serine is replaced by a lysine in mammals (H2AK15), which undergoes an acetyl-monoubiquityl switch to regulate binding of 53BP1 and resection. This regulation seems functionally conserved with budding yeast H2AS15 and 53BP1-homolog Rad9, using different post-translational modifications between organisms but achieving the same function.
Zhaoyuan Niu, Fengling Wang, Shihui Lv, Yingpin Lv, Ming Liu, Lei Fu, Yushuang Yao, Lingzhi Wang, Wei Lin, Fang Yuan
Molecular and Cellular Biology, Volume 41;

Long noncoding RNAs (lncRNAs) have key functions in modulating cervical cancer (CC) genesis and progression. This work focused on exploring lncRNA HNRNPU-AS1's function in CC and the underlying mechanism.
Yihong Huang, Shuo Zheng, Ying Lin, Liming Ke
Molecular and Cellular Biology, Volume 41;

Triple-negative breast cancer (TNBC) is an aggressive histological subtype of breast cancer. It has been reported that the circular RNA (circRNA) circ-ERBB2 (circBase identifier hsa_circ_0007766) is mainly distributed in the cytoplasm of TNBC cells and promotes the proliferation and invasion of TNBC cells.
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