scholarly journals DNA Double Strand Break Repair and Its Control by Nucleosome Remodeling

2022 ◽  
Vol 12 ◽  
Author(s):  
Leonhard Andreas Karl ◽  
Martina Peritore ◽  
Lorenzo Galanti ◽  
Boris Pfander
Keyword(s):  
Strand Break ◽  
Dna Double Strand Breaks ◽  
Cellular Mechanisms ◽  
Dsb Repair ◽  
Nucleosome Remodeling ◽  
Strand Breaks ◽  
Enzymatic Mechanism ◽  
Dna Double Strand Break ◽  
Dna End Resection ◽  
Open Question

DNA double strand breaks (DSBs) are repaired in eukaryotes by one of several cellular mechanisms. The decision-making process controlling DSB repair takes place at the step of DNA end resection, the nucleolytic processing of DNA ends, which generates single-stranded DNA overhangs. Dependent on the length of the overhang, a corresponding DSB repair mechanism is engaged. Interestingly, nucleosomes—the fundamental unit of chromatin—influence the activity of resection nucleases and nucleosome remodelers have emerged as key regulators of DSB repair. Nucleosome remodelers share a common enzymatic mechanism, but for global genome organization specific remodelers have been shown to exert distinct activities. Specifically, different remodelers have been found to slide and evict, position or edit nucleosomes. It is an open question whether the same remodelers exert the same function also in the context of DSBs. Here, we will review recent advances in our understanding of nucleosome remodelers at DSBs: to what extent nucleosome sliding, eviction, positioning and editing can be observed at DSBs and how these activities affect the DSB repair decision.

scholarly journals RAP80 suppresses the vulnerability of R-loops during DNA double-strand break repair

2021 ◽  
Author(s):  
Takaaki Yasuhara ◽  
Reona Kato ◽  
Motohiro Yamauchi ◽  
Yuki Uchihara ◽  
Lee Zou ◽  
...  
Keyword(s):  
Active Regions ◽  
Strand Break ◽  
Double Strand Breaks ◽  
Critical Component ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Dsb Repair ◽  
Strand Breaks ◽  
Chromosome Translocations ◽  
Dna Double Strand Break

AbstractR-loops, consisting of ssDNA and DNA-RNA hybrids, are potentially vulnerable unless they are appropriately processed. Recent evidence suggests that R-loops can form in the proximity of DNA double-strand breaks (DSBs) within transcriptionally active regions. Yet, how the vulnerability of R-loops is overcome during DSB repair remains unclear. Here, we identify RAP80 as a factor suppressing the vulnerability of ssDNA in R-loops and chromosome translocations and deletions during DSB repair. Mechanistically, RAP80 prevents unscheduled nucleolytic processing of ssDNA in R-loops by CtIP. This mechanism promotes efficient DSB repair via transcription-associated end-joining dependent on BRCA1, Polθ, and LIG1/3. Thus, RAP80 suppresses the vulnerability of R-loops during DSB repair, thereby precluding genomic abnormalities in a critical component of the genome caused by deleterious R-loop processing.

scholarly journals The ubiquitin landscape at DNA double-strand breaks

2009 ◽  
Vol 187 (3) ◽  
pp. 319-326 ◽  
Author(s):  
Troy E. Messick ◽  
Roger A. Greenberg
Keyword(s):  
Dna Damage ◽  
Cancer Susceptibility ◽  
Strand Break ◽  
Dna Double Strand Breaks ◽  
Dsb Repair ◽  
Checkpoint Signaling ◽  
Strand Breaks ◽  
Parallel Processes ◽  
Dna Double Strand Break ◽  
Cellular Dna

The intimate relationship between DNA double-strand break (DSB) repair and cancer susceptibility has sparked profound interest in how transactions on DNA and chromatin surrounding DNA damage influence genome integrity. Recent evidence implicates a substantial commitment of the cellular DNA damage response machinery to the synthesis, recognition, and hydrolysis of ubiquitin chains at DNA damage sites. In this review, we propose that, in order to accommodate parallel processes involved in DSB repair and checkpoint signaling, DSB-associated ubiquitin structures must be nonuniform, using different linkages for distinct functional outputs. We highlight recent advances in the study of nondegradative ubiquitin signaling at DSBs, and discuss how recognition of different ubiquitin structures may influence DNA damage responses.

scholarly journals Beyond reversal: ubiquitin and ubiquitin-like proteases and the orchestration of the DNA double strand break repair response

2019 ◽  
Vol 47 (6) ◽  
pp. 1881-1893
Author(s):  
Alexander J. Garvin
Keyword(s):  
Protein Interactions ◽  
Cellular Response ◽  
Strand Break ◽  
Central Component ◽  
Protein Protein Interactions ◽  
Dna Double Strand Breaks ◽  
Dsb Repair ◽  
Post Translational Modifications ◽  
Strand Breaks ◽  
Dna Double Strand Break

The cellular response to genotoxic DNA double strand breaks (DSBs) uses a multitude of post-translational modifications to localise, modulate and ultimately clear DNA repair factors in a timely and accurate manner. Ubiquitination is well established as vital to the DSB response, with a carefully co-ordinated pathway of histone ubiquitination events being a central component of DSB signalling. Other ubiquitin-like modifiers (Ubl) including SUMO and NEDD8 have since been identified as playing important roles in DSB repair. In the last five years ∼20 additional Ub/Ubl proteases have been implicated in the DSB response. The number of proteases identified highlights the complexity of the Ub/Ubl signal present at DSBs. Ub/Ubl proteases regulate turnover, activity and protein–protein interactions of DSB repair factors both catalytically and non-catalytically. This not only ensures efficient repair of breaks but has a role in channelling repair into the correct DSB repair sub-pathways. Ultimately Ub/Ubl proteases have essential roles in maintaining genomic stability. Given that deficiencies in many Ub/Ubl proteases promotes sensitivity to DNA damaging chemotherapies, they could be attractive targets for cancer treatment.

scholarly journals HP1β Chromo Shadow Domain facilitates H2A ubiquitination for BRCA1 recruitment at DNA double-strand breaks

2022 ◽  
Author(s):  
Tej Pandita ◽  
Vijay Kumari Charaka ◽  
Sharmistha Chakraborty ◽  
Chi-Lin Tsai ◽  
Xiaoyan Wang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Genome Stability ◽  
Strand Break ◽  
Dna Double Strand Breaks ◽  
Dsb Repair ◽  
Strand Breaks ◽  
Damage Repair ◽  
Dna Double Strand Break ◽  
Assembly Factor ◽  
Chromo Shadow Domain

Efficient DNA double strand break (DSB) repair by homologous recombination (HR), as orchestrated by histone and non-histone proteins, is critical to genome stability, replication, transcription, and cancer avoidance. Here we report that Heterochromatin Protein1 beta (HP1β) acts as a key component of the HR DNA resection step by regulating BRCA1 enrichment at DNA damage sites, a function largely dependent on the HP1β chromo shadow domain (CSD). HP1β itself is enriched at DSBs within gene-rich regions through a CSD interaction with Chromatin Assembly Factor 1 (CAF1) and HP1β depletion impairs subsequent BRCA1 enrichment. An added interaction of the HP1β CSD with the Polycomb Repressor Complex 1 ubiquitinase component RING1A facilitates BRCA1 recruitment by increasing H2A lysine 118-119 ubiquitination, a marker for BRCA1 recruitment. Our findings reveal that HP1β interactions, mediated through its CSD with RING1A, promote H2A ubiquitination and facilitate BRCA1 recruitment at DNA damage sites, a critical step in DSB repair by the HR pathway. These collective results unveil how HP1β is recruited to DSBs in gene-rich regions and how HP1β subsequently promotes BRCA1 recruitment to further HR DNA damage repair by stimulating CtIP-dependent resection.

scholarly journals Kinesin Kif2C in regulation of DNA double strand break dynamics and repair

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Songli Zhu ◽  
Mohammadjavad Paydar ◽  
Feifei Wang ◽  
Yanqiu Li ◽  
Ling Wang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Mammalian Cells ◽  
Strand Break ◽  
Dna Double Strand Breaks ◽  
Dsb Repair ◽  
Strand Breaks ◽  
Dna Double Strand Break ◽  
Egg Extracts ◽  
Xenopus Egg ◽  
Xenopus Egg Extracts

DNA double strand breaks (DSBs) have detrimental effects on cell survival and genomic stability, and are related to cancer and other human diseases. In this study, we identified microtubule-depolymerizing kinesin Kif2C as a protein associated with DSB-mimicking DNA templates and known DSB repair proteins in Xenopus egg extracts and mammalian cells. The recruitment of Kif2C to DNA damage sites was dependent on both PARP and ATM activities. Kif2C knockdown or knockout led to accumulation of endogenous DNA damage, DNA damage hypersensitivity, and reduced DSB repair via both NHEJ and HR. Interestingly, Kif2C depletion, or inhibition of its microtubule depolymerase activity, reduced the mobility of DSBs, impaired the formation of DNA damage foci, and decreased the occurrence of foci fusion and resolution. Taken together, our study established Kif2C as a new player of the DNA damage response, and presented a new mechanism that governs DSB dynamics and repair.

scholarly journals The mRNA export adaptor Yra1 contributes to DNA double-strand break repair through its C-box domain

2018 ◽  
Author(s):  
Valentina Infantino ◽  
Evelina Tutucci ◽  
Noël Yeh Martin ◽  
Audrey Zihlmann ◽  
Varinia García-Molinero ◽  
...  
Keyword(s):  
Mrna Export ◽  
Strand Break ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Nuclear Pores ◽  
Dsb Repair ◽  
Telomere Shortening ◽  
Strand Breaks ◽  
Dna Double Strand Break ◽  
Evolutionarily Conserved

ABSTRACTYra1 is an mRNA export adaptor involved in mRNA biogenesis and export in S. cerevisiae. Yra1 overexpression was recently shown to promote accumulation of DNA:RNA hybrids favoring DNA double strand breaks (DSB), cell senescence and telomere shortening, via an unknown mechanism. Yra1 was also identified at an HO-induced DSB and Yra1 depletion causes defects in DSB repair. Previous work from our laboratory showed that Yra1 ubiquitination by Tom1 is important for mRNA export. Interestingly, we found that Yra1 is also ubiquitinated by the SUMO-targeted ubiquitin ligases Slx5-Slx8 implicated in the interaction of irreparable DSB with nuclear pores. Here we show that Yra1 binds an HO-induced irreparable DSB. Importantly, a Yra1 mutant lacking the evolutionarily conserved C-box is not recruited to an HO-induced irreparable DSB and becomes lethal under DSB induction in a HO-cut reparable system. Together, the data provide evidence that Yra1 plays a crucial role in DSB repair via homologous recombination. Unexpectedly, while the Yra1 C-box is essential, Yra1 sumoylation and/or ubiquitination are dispensable in this process.

scholarly journals LIN37-DREAM prevents DNA end resection and homologous recombination at DNA double-strand breaks in quiescent cells

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Bo-Ruei Chen ◽  
Yinan Wang ◽  
Anthony Tubbs ◽  
Dali Zong ◽  
Faith C Fowler ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Strand Break ◽  
Dna Double Strand Breaks ◽  
Independent Manner ◽  
Strand Breaks ◽  
Quiescent Cells ◽  
Dna Double Strand Break ◽  
Dna End Resection ◽  
Brca1 Brca2 ◽  
End Resection

DNA double-strand break (DSB) repair by homologous recombination (HR) is thought to be restricted to the S- and G2- phases of the cell cycle in part due to 53BP1 antagonizing DNA end resection in G1-phase and non-cycling quiescent (G0) cells. Here, we show that LIN37, a component of the DREAM transcriptional repressor, functions in a 53BP1-independent manner to prevent DNA end resection and HR in G0 cells. Loss of LIN37 leads to the expression of HR proteins, including BRCA1, BRCA2, PALB2, and RAD51, and promotes DNA end resection in G0 cells even in the presence of 53BP1. In contrast to 53BP1-deficiency, DNA end resection in LIN37-deficient G0 cells depends on BRCA1 and leads to RAD51 filament formation and HR. LIN37 is not required to protect DNA ends in cycling cells at G1-phase. Thus, LIN37 regulates a novel 53BP1-independent cell phase-specific DNA end protection pathway that functions uniquely in quiescent cells.

scholarly journals hMre11 and hRad50 nuclear foci are induced during the normal cellular response to DNA double-strand breaks.

1997 ◽  
Vol 17 (10) ◽  
pp. 6087-6096 ◽  
Author(s):  
R S Maser ◽  
K J Monsen ◽  
B E Nelms ◽  
J H Petrini
Keyword(s):  
Cellular Response ◽  
Strand Break ◽  
Response To Treatment ◽  
Dna Double Strand Breaks ◽  
Dsb Repair ◽  
Focus Formation ◽  
Strand Breaks ◽  
Dna Double Strand Break ◽  
Repair Protein ◽  
Nuclear Foci

We previously identified a conserved multiprotein complex that includes hMre11 and hRad50. In this study, we used immunofluorescence to investigate the role of this complex in DNA double-strand break (DSB) repair. hMre11 and hRad50 form discrete nuclear foci in response to treatment with DSB-inducing agents but not in response to UV irradiation. hMre11 and hRad50 foci colocalize after treatment with ionizing radiation and are distinct from those of the DSB repair protein, hRad51. Our data indicate that an irradiated cell is competent to form either hMre11-hRad50 foci or hRad51 foci, but not both. The multiplicity of hMre11 and hRad50 foci is much higher in the DSB repair-deficient cell line 180BR than in repair-proficient cells. hMre11-hRad50 focus formation is markedly reduced in cells derived from ataxia-telangiectasia patients, whereas hRad51 focus formation is markedly increased. These experiments support genetic evidence from Saccharomyces cerevisiae indicating that Mre11-Rad50 have roles distinct from that of Rad51 in DSB repair. Further, these data indicate that hMre11-hRad50 foci form in response to DNA DSBs and are dependent upon a DNA damage-induced signaling pathway.

scholarly journals DNA Double-Strand Break Repair: All Roads Lead to HeterochROMAtin Marks

2021 ◽  
Vol 12 ◽  
Author(s):  
Pierre Caron ◽  
Enrico Pobega ◽  
Sophie E. Polo
Keyword(s):  
De Novo ◽  
Current Knowledge ◽  
Strand Break ◽  
Double Strand Breaks ◽  
Genome Integrity ◽  
Dna Double Strand Breaks ◽  
Dsb Repair ◽  
Strand Breaks ◽  
Dna Double Strand Break ◽  
The Impact

In response to DNA double-strand breaks (DSBs), chromatin modifications orchestrate DNA repair pathways thus safeguarding genome integrity. Recent studies have uncovered a key role for heterochromatin marks and associated factors in shaping DSB repair within the nucleus. In this review, we present our current knowledge of the interplay between heterochromatin marks and DSB repair. We discuss the impact of heterochromatin features, either pre-existing in heterochromatin domains or de novo established in euchromatin, on DSB repair pathway choice. We emphasize how heterochromatin decompaction and mobility further support DSB repair, focusing on recent mechanistic insights into these processes. Finally, we speculate about potential molecular players involved in the maintenance or the erasure of heterochromatin marks following DSB repair, and their implications for restoring epigenome function and integrity.

scholarly journals Alternative Lengthening of Telomeres: Lessons to Be Learned from Telomeric DNA Double-Strand Break Repair

Genes ◽  
2021 ◽  
Vol 12 (11) ◽  
pp. 1734
Author(s):  
Thomas Kent ◽  
David Clynes
Keyword(s):  
Strand Break ◽  
Dna Double Strand Breaks ◽  
Telomeric Dna ◽  
Dsb Repair ◽  
Alternative Lengthening Of Telomeres ◽  
Strand Breaks ◽  
Alternative Lengthening ◽  
Dna Double Strand Break ◽  
Cycle Dependent ◽  
Telomere Lengthening

The study of the molecular pathways underlying cancer has given us important insights into how breaks in our DNA are repaired and the dire consequences that can occur when these processes are perturbed. Extensive research over the past 20 years has shown that the key molecular event underpinning a subset of cancers involves the deregulated repair of DNA double-strand breaks (DSBs) at telomeres, which in turn leads to telomere lengthening and the potential for replicative immortality. Here we discuss, in-depth, recent major breakthroughs in our understanding of the mechanisms underpinning this pathway known as the alternative lengthening of telomeres (ALT). We explore how this gives us important insights into how DSB repair at telomeres is regulated, with relevance to the cell-cycle-dependent regulation of repair, repair of stalled replication forks and the spatial regulation of DSB repair.

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