scholarly journals ATRX proximal protein associations boast roles beyond histone deposition

PLoS Genetics ◽  
2021 ◽  
Vol 17 (11) ◽  
pp. e1009909
Author(s):  
William A. Scott ◽  
Erum Z. Dhanji ◽  
Boris J. A. Dyakov ◽  
Ema S. Dreseris ◽  
Jonathon S. Asa ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Protein Interactions ◽  
Chromatin Remodelling ◽  
Response Factor ◽  
Proteomic Screen ◽  
Alternative Lengthening ◽  
Damage Response ◽  
Histone Deposition ◽  
Ribosome Biosynthesis

The ATRX ATP-dependent chromatin remodelling/helicase protein associates with the DAXX histone chaperone to deposit histone H3.3 over repetitive DNA regions. Because ATRX-protein interactions impart functions, such as histone deposition, we used proximity-dependent biotinylation (BioID) to identify proximal associations for ATRX. The proteomic screen captured known interactors, such as DAXX, NBS1, and PML, but also identified a range of new associating proteins. To gauge the scope of their roles, we examined three novel ATRX-associating proteins that likely differed in function, and for which little data were available. We found CCDC71 to associate with ATRX, but also HP1 and NAP1, suggesting a role in chromatin maintenance. Contrastingly, FAM207A associated with proteins involved in ribosome biosynthesis and localized to the nucleolus. ATRX proximal associations with the SLF2 DNA damage response factor help inhibit telomere exchanges. We further screened for the proteomic changes at telomeres when ATRX, SLF2, or both proteins were deleted. The loss caused important changes in the abundance of chromatin remodelling, DNA replication, and DNA repair factors at telomeres. Interestingly, several of these have previously been implicated in alternative lengthening of telomeres. Altogether, this study expands the repertoire of ATRX-associating proteins and functions.

scholarly journals Targeting Protein-Protein Interactions in the DNA Damage Response Pathways for Cancer Chemotherapy

2021 ◽  
Author(s):  
Kerry Silva McPherson ◽  
Dmitry Korzhnev
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Protein Interactions ◽  
Cell Cycle Progression ◽  
Protein Protein Interactions ◽  
Cycle Progression ◽  
Damage Recognition ◽  
Damage Response ◽  
Cellular Dna ◽  
Dna Damage Recognition

Cellular DNA damage response (DDR) is an extensive signaling network that orchestrates DNA damage recognition, repair and avoidance, cell cycle progression and cell death. DDR alternation is a hallmark of...

scholarly journals The CHD6 chromatin remodeler is an oxidative DNA damage response factor

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Shaun Moore ◽  
N. Daniel Berger ◽  
Martijn S. Luijsterburg ◽  
Cortt G. Piett ◽  
Fintan K. T. Stanley ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Oxidative Dna Damage ◽  
Response Factor ◽  
Chromatin Remodeler ◽  
Damage Response

Structural basis for phosphorylation-dependent signaling in the DNA-damage response

2005 ◽  
Vol 83 (6) ◽  
pp. 721-727 ◽  
Author(s):  
R Scott Williams ◽  
Nina Bernstein ◽  
Megan S Lee ◽  
Melissa L Rakovszky ◽  
Diana Cui ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Protein Interactions ◽  
Tandem Repeats ◽  
Strand Break ◽  
Structural Basis ◽  
Fha Domain ◽  
Flexible Mode ◽  
Polynucleotide Kinase ◽  
Damage Response

The response of eukaryotic cells to DNA damage requires a multitude of protein–protein interactions that mediate the ordered repair of the damage and the arrest of the cell cycle until repair is complete. Two conserved protein modules, BRCT and forkhead-associated (FHA) domains, play key roles in the DNA-damage response as recognition elements for nuclear Ser/Thr phosphorylation induced by DNA-damage-responsive kinases. BRCT domains, first identified at the C-terminus of BRCA1, often occur as multiple tandem repeats of individual BRCT modules. Our recent structural and functional work has revealed how BRCT repeats recognize phosphoserine protein targets. It has also revealed a secondary binding pocket at the interface between tandem repeats, which recognizes the amino-acid 3 residues C-terminal to the phosphoserine. We have also studied the molecular function of the FHA domain of the DNA repair enzyme, polynucleotide kinase (PNK). This domain interacts with threonine-phosphorylated XRCC1 and XRCC4, proteins responsible for the recruitment of PNK to sites of DNA-strand-break repair. Our studies have revealed a flexible mode of recognition that allows PNK to interact with numerous negatively charged substrates.Key words: BRCA1, BRCT, PNK, FHA, polynucleotide kinase, breast cancer, phosphopeptide-protein interactions, DNA damage response.

scholarly journals BRIT1/MCPH1 links chromatin remodelling to DNA damage response

2009 ◽  
Vol 11 (7) ◽  
pp. 865-872 ◽  
Author(s):  
Guang Peng ◽  
Eun-Kyoung Yim ◽  
Hui Dai ◽  
Andrew P. Jackson ◽  
Ineke van der Burgt ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Chromatin Remodelling ◽  
Damage Response

scholarly journals FANCM suppresses DNA replication stress at ALT telomeres by disrupting TERRA R-loops

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Xiaolei Pan ◽  
Yun Chen ◽  
Beena Biju ◽  
Naveed Ahmed ◽  
Joyce Kong ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Replication Stress ◽  
Checkpoint Kinases ◽  
Alternative Lengthening ◽  
Pml Bodies ◽  
Damage Response ◽  
Dna Replication Stress ◽  
The Many ◽  
Break Induced Replication

AbstractCancer cells maintain their telomeres by either re-activating telomerase or adopting the homologous recombination (HR)-based Alternative Lengthening of Telomere (ALT) pathway. Among the many prominent features of ALT cells, C-circles (CC) formation is considered to be the most specific and quantifiable biomarker of ALT. However, the molecular mechanism behind the initiation and maintenance of CC formation in ALT cells is still largely unknown. We reported previously that depletion of the FANCM complex (FANCM-FAAP24-MHF1&2) in ALT cells induced pronounced replication stress, which primarily takes place at their telomeres. Here, we characterized the changes in ALT associated phenotypes in cells deficient of the FANCM complex. We found that depletion of FAAP24 or FANCM, but not MHF1&2, induces a dramatic increase of CC formation. Most importantly, we identified multiple DNA damage response (DDR) and DNA repair pathways that stimulate the dramatic increase of CC formation in FANCM deficient cells, including the dissolvase complex (BLM-TOP3A-RMI1/2, or BTR), DNA damage checkpoint kinases (ATR and Chk1), HR proteins (BRCA2, PALB2, and Rad51), as well as proteins involved in Break-Induced Replication (BIR) (POLD1 and POLD3). In addition, FANCD2, another Fanconi Anemia (FA) protein, is also required for CC formation, likely through promoting the recruitment of BLM to the replication stressed ALT telomeres. Finally, we demonstrated that TERRA R-loops accumulate at telomeres in FANCM deficient ALT cells and downregulation of which attenuates the ALT-associated PML bodies (APBs), replication stress and CC formation. Taken together, our data suggest that FANCM prevents replisomes from stalling/collapsing at ALT telomeres by disrupting TERRA R-loops.

scholarly journals Recent advancements in the discovery of protein–protein interaction inhibitors of replication protein A

MedChemComm ◽  
2017 ◽  
Vol 8 (2) ◽  
pp. 259-267 ◽  
Author(s):  
James D. Patrone ◽  
Alex G. Waterson ◽  
Stephen W. Fesik
Keyword(s):  
Dna Damage ◽  
Recent Work ◽  
Dna Damage Response ◽  
Protein Interaction ◽  
Protein Interactions ◽  
Protein A ◽  
Replication Protein A ◽  
Protein Protein Interactions ◽  
Protein Protein Interaction ◽  
Damage Response

This review summarizes recent work directed toward the discovery of selective inhibitors of the protein–protein interactions between RPA and proteins involved in the initiation of DNA damage response pathways.

scholarly journals DAXX-ATRX-H3.3 Regulation of p53 Chromatin Binding and DNA Damage Response

2021 ◽  
Author(s):  
Nitish Gulve ◽  
Zhong Deng ◽  
Samantha Soldan ◽  
Olga Vladimirova ◽  
Jayamanna Wickramasinghe ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Chromatin Binding ◽  
Rna Seq ◽  
Loss Of Function ◽  
Glioblastoma Cells ◽  
Histone H3.3 ◽  
Alternative Lengthening ◽  
Damage Response ◽  
Chaperone Complex

Abstract DAXX and ATRX are tumor suppressor proteins that form a histone H3.3 chaperone complex and are frequently mutated in cancers with the alternative lengthening of telomeres (ALT), such as pediatric glioblastoma. Rapid loss of function of either DAXX or ATRX are not by themselves sufficient to induce the ALT phenotype. However, cells lacking DAXX or ATRX can be readily selected for ALT-like features. Here, we show that DAXX and ATRX null glioblastoma cells with ALT-like features have defects in p53 chromatin binding and DNA damage response regulation. RNA-seq analysis of DAXX or ATRX null U87 glioblastoma cells with ALT-like features revealed that p53 pathway is among perturbed. ALT-selected DAXX and ATRX-null cells had aberrant response to DNA damaging agent etoposide. Both DAXX and ATRX-null ALT cells showed a loss of p53 binding at a subset of response elements. Complementation of DAXX null cells with a wild-type DAXX transgene rescued p53 binding and transcription, while the tumor associated mutation L130R that disrupts ATRX binding was incapable of rescuing p53 chromatin binding. We show that histone H3.3 binding is reduced in DAXX-null cells especially at subtelomeric p53 binding sites and telomere repeats. These findings indicate that DAXX and ATRX function to enable p53 chromatin binding through modulation of histone H3.3 binding, especially at sub-telomeric sites.

Sign in / Sign up

Export Citation Format

Share Document