scholarly journals DNA end-resection in highly accessible chromatin produces a toxic break

2019 ◽  
Author(s):  
Jeroen van den Berg ◽  
Stacey E.P. Joosten ◽  
YongSoo Kim ◽  
Anna G. Manjón ◽  
Lenno Krenning ◽  
...  
Keyword(s):  
Strand Break ◽  
Open Chromatin ◽  
End Joining ◽  
Close Proximity ◽  
Damage Response ◽  
Hypersensitive Sites ◽  
Dna End Resection ◽  
Non Homologous End Joining ◽  
End Resection ◽  
Accessible Chromatin

AbstractOf all damage occurring to DNA, the double strand break (DSB) is the most toxic lesion. Luckily, cells have developed multiple repair pathways to cope with these lesions. These different pathways compete for the same break, and the location of the break can influence this competition. However, the exact contribution of break location in repair pathway preference is not fully understood. We observe that most breaks prefer classical non-homologous end-joining, whereas some depend on DNA end-resection for their repair. Surprisingly, we find that for a subset of these sites, the activation of resection-dependent repair induces a detrimental DNA damage response. These sites exhibit extensive DNA end-resection due to improper recruitment of 53BP1 and the Shieldin complex due to low levels of H4K20me2. Most of these sites reside in close proximity to DNAseI hypersensitive sites. Compacting or removing these regions reduces extensive DNA end-resection and restores normal repair. Taken together, we found that DSB in open chromatin is highly toxic, due to the improper activity of 53BP1 and Shieldin, resulting in extensive DNA end-resection.

scholarly journals Nucleosome disassembly during human non-homologous end joining followed by concerted HIRA- and CAF-1-dependent reassembly

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Xuan Li ◽  
Jessica K Tyler
Keyword(s):  
Strand Break ◽  
End Joining ◽  
Efficient Removal ◽  
Dsb Repair ◽  
Dna Double Strand Break ◽  
Dna End Resection ◽  
Non Homologous End Joining ◽  
Nucleosome Disassembly ◽  
End Resection ◽  
Assembly Pathways

The cell achieves DNA double-strand break (DSB) repair in the context of chromatin structure. However, the mechanisms used to expose DSBs to the repair machinery and to restore the chromatin organization after repair remain elusive. Here we show that induction of a DSB in human cells causes local nucleosome disassembly, apparently independently from DNA end resection. This efficient removal of histone H3 from the genome during non-homologous end joining was promoted by both ATM and the ATP-dependent nucleosome remodeler INO80. Chromatin reassembly during DSB repair was dependent on the HIRA histone chaperone that is specific to the replication-independent histone variant H3.3 and on CAF-1 that is specific to the replication-dependent canonical histones H3.1/H3.2. Our data suggest that the epigenetic information is re-established after DSB repair by the concerted and interdependent action of replication-independent and replication-dependent chromatin assembly pathways.

scholarly journals Regulation of DNA Double-Strand Break Repair by Non-Coding RNAs

2018 ◽  
Author(s):  
Roopa Thapar
Keyword(s):  
Strand Break ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Strand Breaks ◽  
Dna Double Strand Break ◽  
Protein Dna Interactions ◽  
Damage Response ◽  
Non Coding Rnas ◽  
Non Homologous End Joining

DNA double-strand breaks (DSBs) are deleterious lesions that are generated in response to ionizing radiation or replication fork collapse that can lead to genomic instability and cancer.  Eukaryotes have evolved two major pathways, namely homologous recombination (HR) and non-homologous end joining (NHEJ) to repair DSBs.  Whereas the roles of protein-DNA interactions in HR and NHEJ have been fairly well defined, the functions of small and long non-coding RNAs and RNA-DNA hybrids in the DNA damage response is just beginning to be elucidated.  This review summarizes recent discoveries on the identification of non-coding RNAs and RNA-mediated regulation of DSB repair

scholarly journals Regulation of DNA Double-Strand Break Repair by Non-Coding RNAs

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 2789 ◽  
Author(s):  
Roopa Thapar
Keyword(s):  
Strand Break ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Strand Breaks ◽  
Dna Double Strand Break ◽  
Protein Dna Interactions ◽  
Damage Response ◽  
Non Coding Rnas ◽  
Non Homologous End Joining

DNA double-strand breaks (DSBs) are deleterious lesions that are generated in response to ionizing radiation or replication fork collapse that can lead to genomic instability and cancer. Eukaryotes have evolved two major pathways, namely homologous recombination (HR) and non-homologous end joining (NHEJ) to repair DSBs. Whereas the roles of protein-DNA interactions in HR and NHEJ have been fairly well defined, the functions of small and long non-coding RNAs and RNA-DNA hybrids in the DNA damage response is just beginning to be elucidated. This review summarizes recent discoveries on the identification of non-coding RNAs and RNA-mediated regulation of DSB repair.

scholarly journals Multifunctional properties of Nej1XLF C-terminus promote end-joining and impact DNA double-strand break repair pathway choice

2022 ◽  
Author(s):  
Aditya Mojumdar ◽  
Nancy Adam ◽  
Jennifer A Cobb
Keyword(s):  
Strand Break ◽  
Double Strand Break ◽  
Repair Pathway ◽  
End Joining ◽  
C Terminus ◽  
Dna Double Strand Break ◽  
Canonical Pathways ◽  
Pathway Choice ◽  
Non Homologous End Joining ◽  
End Resection

A DNA double strand break (DSB) is primarily repaired by one of two canonical pathways, non-homologous end-joining (NHEJ) and homologous recombination (HR). NHEJ requires no or minimal end processing for ligation, whereas HR requires 5 end resection followed by a search for homology. The main event that determines the mode of repair is the initiation of 5 resection because if resection starts, then NHEJ cannot occur. Nej1 is a canonical NHEJ factor that functions at the cross-roads of repair pathway choice and prior to its function in stimulating Dnl4 ligase. Nej1 competes with Dna2, inhibiting its recruitment to DSBs and thereby inhibiting resection. The highly conserved C-terminal region (CTR) of Nej1 (330- 338) is important for two events that drive NHEJ, stimulating ligation and inhibiting resection, but it is dispensable for end-bridging. By combining nej1 point mutants with nuclease-dead dna2-1, we find that Nej1-F335 is essential for end-joining whereas V338 promotes NHEJ indirectly through inhibiting Dna2-mediated resection.

scholarly journals The non-homologous end joining factor Ku orchestrates replication fork resection and fine-tunes Rad51-mediated fork restart

2017 ◽  
Author(s):  
Ana Teixeira-Silva ◽  
Anissia Ait Saada ◽  
Ismail Iraqui ◽  
Marina Charlotte Nocente ◽  
Karine Fréon ◽  
...  
Keyword(s):  
Replication Fork ◽  
Double Strand Breaks ◽  
Fine Tuning ◽  
List Type ◽  
End Joining ◽  
Strand Breaks ◽  
Replication Restart ◽  
Dna End Resection ◽  
Non Homologous End Joining ◽  
End Resection

AbstractReplication requires Homologous Recombination (HR) to stabilize and restart terminally-arrested forks. HR-mediated fork processing requires single stranded DNA (ssDNA) gaps and not necessarily Double Strand Breaks. We used genetic and molecular assays to investigate fork-resection and restart at dysfunctional, unbroken forks in Schizosaccharomyces pombe. We found that fork-resection is a two-step process coordinated by the non-homologous end joining factor Ku. An initial resection mediated by MRN/Ctp1 removes Ku from terminally-arrested forks, generating ~ 110 bp sized gaps obligatory for subsequent Exo1-mediated long-range resection and replication restart. The lack of Ku results in slower fork restart, excessive resection, and impaired RPA recruitment. We propose that terminally-arrested forks undergo fork reversal, providing a single DNA end for Ku binding which primes RPA-coated ssDNA. We uncover an unprecedented role for Ku in orchestrating resection of unbroken forks and in fine-tuning HR-mediated replication restart.Ku orchestrates a two-steps DNA end-resection of terminally-arrested and unbroken forksMRN/Ctp1 removes Ku from terminally-arrested forks to initiate fork-resectiona ~110 bp sized ssDNA gap is sufficient and necessary to promote fork restart.The lack of Ku decreases ssDNA RPA-coating, and slows down replication fork restart.

scholarly journals Competing roles of DNA end resection and non-homologous end joining functions in the repair of replication-born double-strand breaks by sister-chromatid recombination

2012 ◽  
Vol 41 (3) ◽  
pp. 1669-1683 ◽  
Author(s):  
Sandra Muñoz-Galván ◽  
Ana López-Saavedra ◽  
Stephen P. Jackson ◽  
Pablo Huertas ◽  
Felipe Cortés-Ledesma ◽  
...  
Keyword(s):  
Sister Chromatid ◽  
Double Strand Breaks ◽  
End Joining ◽  
Strand Breaks ◽  
Dna End Resection ◽  
Non Homologous End Joining ◽  
End Resection ◽  
Sister Chromatid Recombination
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