Targeting DNA damage response pathways in cancer

Nature reviews. Cancer, Journal Year: 2022, Volume and Issue: 23(2), P. 78 - 94

Published: Dec. 5, 2022

Language: Английский

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DNA repair defects in cancer and therapeutic opportunities

Genes & Development, Journal Year: 2022, Volume and Issue: 36(5-6), P. 278 - 293

Published: March 1, 2022

DNA repair and damage signaling pathways are critical for the maintenance of genomic stability. Defects contribute to tumorigenesis, but also render cancer cells vulnerable reliant on remaining activities. Here, we review major classes defects in cancer, instability that they give rise to, therapeutic strategies exploit resulting vulnerabilities. Furthermore, discuss impacts both targeted therapy immunotherapy, highlight emerging principles targeting therapy.

Language: Английский

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H2B Lys34 Ubiquitination Induces Nucleosome Distortion to Stimulate Dot1L Activity

Nature Chemical Biology, Journal Year: 2022, Volume and Issue: 18(9), P. 972 - 980

Published: June 23, 2022

Language: Английский

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Synovial sarcoma X breakpoint 1 protein uses a cryptic groove to selectively recognize H2AK119Ub nucleosomes

Nature Structural & Molecular Biology, Journal Year: 2024, Volume and Issue: 31(2), P. 300 - 310

Published: Jan. 4, 2024

Language: Английский

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MoDAFold: a strategy for predicting the structure of missense mutant protein based on AlphaFold2 and molecular dynamics

Briefings in Bioinformatics, Journal Year: 2024, Volume and Issue: 25(2)

Published: Jan. 22, 2024

Abstract Protein structure prediction is a longstanding issue crucial for identifying new drug targets and providing mechanistic understanding of protein functions. To enhance the progress in this field, spectrum computational methodologies has been cultivated. AlphaFold2 exhibited exceptional precision predicting wild-type structures, with performance exceeding that other methods. However, structures missense mutant proteins using remains challenging due to intricate substantial structural alterations caused by minor sequence variations proteins. Molecular dynamics (MD) validated precisely capturing changes amino acid interactions attributed mutations. Therefore, first time, strategy entitled ‘MoDAFold’ was proposed improve accuracy reliability combining MD. Multiple case studies have confirmed superior MoDAFold compared methods, particularly AlphaFold2.

Language: Английский

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Immediate-Early, Early, and Late Responses to DNA Double Stranded Breaks

Frontiers in Genetics, Journal Year: 2022, Volume and Issue: 13

Published: Jan. 31, 2022

Loss or rearrangement of genetic information can result from incorrect responses to DNA double strand breaks (DSBs). The cellular DSBs encompass a range highly coordinated events designed detect and respond appropriately the damage, thereby preserving genomic integrity. In analogy with occurring during viral infection, we appropriate terms Immediate-Early, Early, Late describe pre-repair DSBs. A distinguishing feature Immediate-Early response is that large protein condensates form Early are resolved upon repair, termed foci, not visible. encompasses initial lesion sensing, involving poly (ADP-ribose) polymerases (PARPs), KU70/80, MRN, as well rapid repair by so-called 'fast-kinetic' canonical non-homologous end joining (cNHEJ). Initial binding PARPs KU70/80 complex appears be mutually exclusive at easily ligatable repaired efficiently fast-kinetic cNHEJ; process PARP-, ATM-, 53BP1-, Artemis-, resection-independent. However, more requiring processing, ensuing dynamic PARylation (polyADP ribosylation) many substrates may aid recruitment both MRN Complex rely response, largely defined ATM-dependent focal signalling molecules into condensates, regulated chromatin dynamics. Finally, integrates cell cycle phase, context, type DSB determine pathway choice. Critical choice p53 1 (53BP1) breast cancer associated (BRCA1). additional factors recruited throughout also impact choice, although these remain fully characterised. somehow channels high-fidelity pathway, typically either 'slow-kinetic' cNHEJ homologous recombination (HR). specific components machinery results in cells utilising remaining effect but often cost increased mutagenesis. Here discuss regulation proceeding itself.

Language: Английский

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Synthetic E2-Ub-nucleosome conjugates for studying nucleosome ubiquitination

Chem, Journal Year: 2023, Volume and Issue: 9(5), P. 1221 - 1240

Published: Feb. 13, 2023

Language: Английский

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Histone H2A variants: Diversifying chromatin to ensure genome integrity

Seminars in Cell and Developmental Biology, Journal Year: 2022, Volume and Issue: 135, P. 59 - 72

Published: March 21, 2022

Language: Английский

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Structure of the human UBR5 E3 ubiquitin ligase

Structure, Journal Year: 2023, Volume and Issue: 31(5), P. 541 - 552.e4

Published: April 10, 2023

Language: Английский

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The DNA damage response in the chromatin context: A coordinated process

Current Opinion in Cell Biology, Journal Year: 2023, Volume and Issue: 82, P. 102176 - 102176

Published: June 1, 2023

In the cell nucleus, DNA damage signaling and repair machineries operate on a chromatin substrate, integrity of which is critical for function viability. Here, we review recent advances in deciphering tight coordination between maintenance response (DDR). We discuss how DDR impacts marks, organization mobility, and, turn, alterations actively contribute to DDR, providing additional levels regulation. present our current knowledge molecular bases these processes physiological pathological conditions, also highlight open questions that emerge this expanding field.

Language: Английский

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