Elf1 promotes Rad26’s interaction with lesion-arrested Pol II for transcription-coupled repair DOI Creative Commons
Reta D. Sarsam, Jun Xu, Indrajit Lahiri

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(3)

Published: Jan. 9, 2024

Transcription-coupled nucleotide excision repair (TC-NER) is a highly conserved DNA pathway that removes bulky lesions in the transcribed genome. Cockayne syndrome B protein (CSB), or its yeast ortholog Rad26, has been known for decades to play important roles lesion-recognition steps of TC-NER. Another ELOF1, Elf1, was recently identified as core transcription-coupled factor. How Rad26 distinguishes between RNA polymerase II (Pol II) stalled at lesion other obstacles and what role Elf1 plays this process remains unknown. Here, we present cryo-EM structures Pol II-Rad26 complexes different show uses common mechanism recognize II, with additional interactions when arrested lesion. A structure lesion-arrested bound revealed induces further II. Biochemical genetic data support importance interplay TC-NER initiation. Together, our results provide mechanistic insights into how two factors, Rad26/CSB Elf1/ELOF1, work together initial recognition repair.

Language: Английский

The Unfolded Protein Response: Detecting and Responding to Fluctuations in the Protein-Folding Capacity of the Endoplasmic Reticulum DOI Open Access
G Elif Karagöz, Diego Acosta‐Alvear, Peter Walter

et al.

Cold Spring Harbor Perspectives in Biology, Journal Year: 2019, Volume and Issue: 11(9), P. a033886 - a033886

Published: Jan. 22, 2019

Most of the secreted and plasma membrane proteins are synthesized on membrane-bound ribosomes endoplasmic reticulum (ER). They require engagement ER-resident chaperones foldases that assist in their folding maturation. Since protein homeostasis ER is crucial for cellular function, protein-folding status organelle's lumen continually surveyed by a network signaling pathways, collectively called unfolded response (UPR). Protein-folding imbalances, or "ER stress," detected highly conserved sensors adjust ER's capacity according to physiological needs cell. We review recent developments field have provided new insights into stress-sensing mechanisms used UPR which they integrate various inputs organelle accommodate fluctuations demands.

Language: Английский

Citations

266
Therapy resistance: opportunities created by adaptive responses to targeted therapies in cancer DOI
Marilyne Labrie, Joan S. Brugge, Gordon B. Mills

et al.

Nature reviews. Cancer, Journal Year: 2022, Volume and Issue: 22(6), P. 323 - 339

Published: March 9, 2022

Language: Английский

Citations

227
RNA N6-methyladenosine reader IGF2BP3 regulates cell cycle and angiogenesis in colon cancer DOI Creative Commons
Yang Zhou, Tingfeng Wang, Dejun Wu

et al.

Journal of Experimental & Clinical Cancer Research, Journal Year: 2020, Volume and Issue: 39(1)

Published: Sept. 29, 2020

Abstract Background N6-Methyladenosine (m6A) modification has been implicated in multiple processes for colon cancer development. IGF2BP3 was a newly reported m6A reader, whereas its role remains unclear. Methods The expression of associated enzymes and total level were measured by Western Blotting analysis RNA Methylation Quantification Kit respectively. Cell cycle analyzed flowcytometry. interaction related targets immunoprecipitation (RIP) (MeRIP) assays. Results We investigated all regulated found only the overexpression with progression survival based on Cancer Genome Atlas (TCGA) databases. Additionally, we also demonstrated DNA replication cell cycle. Knockdown significantly repressed percentage S phase as well proliferation. Further research bound to mRNA Cyclin D1 (CCND1, checkpoint G1/S cycle) reduced stability via reading CDS region. Overexpression down-regulated cells completely rescued inhibited similar at VEGF. VEGF reads modification, thus both mRNA. angiogenesis regulating Conclusion CCND1 possible prognosis marker potential therapeutic target cancer.

Language: Английский

Citations

208
Causes and consequences of RNA polymerase II stalling during transcript elongation DOI
Melvin Noé González, Daniel Blears, Jesper Q. Svejstrup

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2020, Volume and Issue: 22(1), P. 3 - 21

Published: Nov. 18, 2020

Language: Английский

Citations

189
PRMT5 function and targeting in cancer DOI Creative Commons
Hyungsoo Kim, Ze’ev A. Ronai

Cell Stress, Journal Year: 2020, Volume and Issue: 4(8), P. 199 - 215

Published: July 24, 2020

Protein methyl transferases play critical roles in numerous regulatory pathways that underlie cancer development, progression and therapy-response. Here we discuss the function of PRMT5, a member nine-member PRMT family, controlling oncogenic processes including tumor intrinsic, as well extrinsic microenvironmental signaling pathways. We PRMT5 effect on histone methylation proteins those involved RNA splicing, cell cycle, death metabolic signaling. In all, highlight importance regulation cancer, which provide foundation for therapeutic modalities targeting PRMT5.

Language: Английский

Citations

164
ROS: Basic Concepts, Sources, Cellular Signaling, and its Implications in Aging Pathways DOI Creative Commons
Arthur José Pontes Oliveira de Almeida, Júlio César Pinheiro Lúcio de Oliveira,

Larisse Virgolino da Silva Pontes

et al.

Oxidative Medicine and Cellular Longevity, Journal Year: 2022, Volume and Issue: 2022, P. 1 - 23

Published: Oct. 19, 2022

Reactive oxygen species (ROS) are bioproducts of cellular metabolism. There is a range molecules with oxidizing properties known as ROS. Despite those being implied negatively in aging and numerous diseases, their key role signaling evident. ROS control several biological processes such inflammation, proliferation, cell death. The redox underlying these events one characteristic the new generation scientists aimed at defining environment. potential, which includes balance sources antioxidant system, implies an important target for understanding cells’ fate derived from signaling. In this review, we summarized chemical, balance, signaling, implications aging.

Language: Английский

Citations

161
Genome-wide RNA polymerase stalling shapes the transcriptome during aging DOI Creative Commons
Àkos Gyenis, Jiang Chang, Joris J. P. G. Demmers

et al.

Nature Genetics, Journal Year: 2023, Volume and Issue: 55(2), P. 268 - 279

Published: Jan. 19, 2023

Gene expression profiling has identified numerous processes altered in aging, but how these changes arise is largely unknown. Here we combined nascent RNA sequencing and polymerase II chromatin immunoprecipitation followed by to elucidate the underlying mechanisms triggering gene wild-type aged mice. We found that 2-year-old liver, 40% of elongating polymerases are stalled, lowering productive transcription skewing transcriptional output a gene-length-dependent fashion. demonstrate this stress caused endogenous DNA damage explains majority aging most mainly postmitotic organs, specifically affecting hallmark pathways such as nutrient sensing, autophagy, proteostasis, energy metabolism, immune function cellular resilience. Age-related evolutionary conserved from nematodes humans. Thus, accumulation stochastic during deteriorates basal transcription, which establishes age-related transcriptome causes dysfunction key pathways, disclosing functionally underlies major aspects normal aging.

Language: Английский

Citations

88
Epigenetics, DNA damage, and aging DOI Creative Commons

Carolina Soto-Palma,

Laura J. Niedernhofer, Christopher Faulk

et al.

Journal of Clinical Investigation, Journal Year: 2022, Volume and Issue: 132(16)

Published: Aug. 14, 2022

Over the course of a human lifespan, genome integrity erodes, leading to an increased abundance several types chromatin changes. The DNA lesions (chemical perturbations nucleotides) increases with age, as does number genomic mutations and transcriptional disruptions caused by replication or transcription those lesions, respectively. At epigenetic level, precise methylation patterns degrade, likely causing increasingly stochastic variations in gene expression. Similarly, tight regulation histone modifications begins unravel. instability these mechanisms allows transposon element reactivation remobilization, further mutations, dysregulation, cytoplasmic fragments. This cumulative promotes cell signaling events that drive fate decisions extracellular communications known disrupt tissue homeostasis regeneration. In this Review, we focus on age-related changes their interactions instigate events.

Language: Английский

Citations

83
PARP1-DNA co-condensation drives DNA repair site assembly to prevent disjunction of broken DNA ends DOI Creative Commons
Nagaraja Chappidi, Thomas Quail,

Simon Doll

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(4), P. 945 - 961.e18

Published: Feb. 1, 2024

DNA double-strand breaks (DSBs) are repaired at DSB sites. How sites assemble and how broken is prevented from separating not understood. Here we uncover that the synapsis of mediated by sensor protein poly(ADP-ribose) (PAR) polymerase 1 (PARP1). Using bottom-up biochemistry, reconstitute functional show form through co-condensation PARP1 multimers with DNA. The co-condensates exert mechanical forces to keep ends together become enzymatically active for PAR synthesis. PARylation promotes release recruitment effectors, such as Fused in Sarcoma, which stabilizes against separation, revealing a finely orchestrated order events primes repair. We provide comprehensive model hierarchical assembly condensates explain end effector proteins damage

Language: Английский

Citations

50
Endogenous aldehyde-induced DNA–protein crosslinks are resolved by transcription-coupled repair DOI Creative Commons
Yasuyoshi Oka, Yuka Nakazawa, Mayuko Shimada

et al.

Nature Cell Biology, Journal Year: 2024, Volume and Issue: 26(5), P. 784 - 796

Published: April 10, 2024

Abstract DNA–protein crosslinks (DPCs) induced by aldehydes interfere with replication and transcription. Hereditary deficiencies in DPC repair aldehyde clearance processes cause progeria, including Ruijs–Aalfs syndrome (RJALS) AMeD (AMeDS) humans. Although the elimination of during has been well established, how cells overcome lesions transcription remains elusive. Here we show that endogenous aldehyde-induced roadblocks are efficiently resolved transcription-coupled (TCR). We develop a high-throughput sequencing technique to measure genome-wide distribution DPCs (DPC-seq). Using proteomics DPC-seq, demonstrate conventional TCR complex as VCP/p97 proteasome required for removal formaldehyde-induced DPCs. TFIIS-dependent cleavage RNAPII transcripts protects against obstacles. Finally, mouse model lacking both confirms accumulation actively transcribed regions. Collectively, our data provide evidence (TC-DPCR) crucial protecting metabolic genotoxin, thus explaining molecular pathogenesis AMeDS other disorders associated defects TCR, such Cockayne syndrome.

Language: Английский

Citations

24