scholarly journals A decade of understanding spatio-temporal regulation of DNA repair by the nuclear architecture

2016 ◽  
Vol 94 (5) ◽  
pp. 433-440 ◽  
Author(s):  
Hicham Saad ◽  
Jennifer A. Cobb
Keyword(s):  
Dna Repair ◽  
Genome Stability ◽  
Nuclear Organization ◽  
Chromosomal Rearrangements ◽  
Nuclear Periphery ◽  
Nuclear Architecture ◽  
Strand Break ◽  
Repair Pathway ◽  
Pathway Choice ◽  
Spatio Temporal

The nucleus is a hub for gene expression and is a highly organized entity. The nucleoplasm is heterogeneous, owing to the preferential localization of specific metabolic factors, which lead to the definition of nuclear compartments or bodies. The genome is organized into chromosome territories, as well as heterochromatin and euchromatin domains. Recent observations have indicated that nuclear organization is important for maintaining genomic stability. For example, nuclear organization has been implicated in stabilizing damaged DNA, repair-pathway choice, and in preventing chromosomal rearrangements. Over the past decade, several studies have revealed that dynamic changes in the nuclear architecture are important during double-strand break repair. Stemming from work in yeast, relocation of a damaged site prior to repair appears to be at least partially conserved in multicellular eukaryotes. In this review, we will discuss genome and nucleoplasm architecture, particularly the importance of the nuclear periphery in genome stability. We will also discuss how the site of relocation regulates repair-pathway choice.

scholarly journals Epigenetic Regulation of DNA Repair Pathway Choice by MacroH2A1 Splice Variants Ensures Genome Stability

2020 ◽  
Vol 79 (5) ◽  
pp. 836-845.e7 ◽  
Author(s):  
Robin Sebastian ◽  
Eri K. Hosogane ◽  
Eric G. Sun ◽  
Andy D. Tran ◽  
William C. Reinhold ◽  
...  
Keyword(s):  
Dna Repair ◽  
Epigenetic Regulation ◽  
Genome Stability ◽  
Splice Variants ◽  
Repair Pathway ◽  
Pathway Choice

scholarly journals Heterochromatin formation via recruitment of DNA repair proteins

2015 ◽  
Vol 26 (7) ◽  
pp. 1395-1410 ◽  
Author(s):  
Jacob G. Kirkland ◽  
Misty R. Peterson ◽  
Christopher D. Still ◽  
Leo Brueggeman ◽  
Namrita Dhillon ◽  
...  
Keyword(s):  
Dna Repair ◽  
Gene Silencing ◽  
Nuclear Organization ◽  
Nuclear Periphery ◽  
Strand Break ◽  
Atm Kinase ◽  
Heterochromatin Formation ◽  
Sir Proteins ◽  
Repair Protein ◽  
Dna Repair Proteins

Heterochromatin formation and nuclear organization are important in gene regulation and genome fidelity. Proteins involved in gene silencing localize to sites of damage and some DNA repair proteins localize to heterochromatin, but the biological importance of these correlations remains unclear. In this study, we examined the role of double-strand-break repair proteins in gene silencing and nuclear organization. We find that the ATM kinase Tel1 and the proteins Mre11 and Esc2 can silence a reporter gene dependent on the Sir, as well as on other repair proteins. Furthermore, these proteins aid in the localization of silenced domains to specific compartments in the nucleus. We identify two distinct mechanisms for repair protein–mediated silencing—via direct and indirect interactions with Sir proteins, as well as by tethering loci to the nuclear periphery. This study reveals previously unknown interactions between repair proteins and silencing proteins and suggests insights into the mechanism underlying genome integrity.

scholarly journals The (Lack of) DNA Double-Strand Break Repair Pathway Choice During V(D)J Recombination

2022 ◽  
Vol 12 ◽  
Author(s):  
Alice Libri ◽  
Timea Marton ◽  
Ludovic Deriano
Keyword(s):  
Dna Repair ◽  
Gene Diversity ◽  
Receptor Gene ◽  
Strand Break ◽  
Repair Pathway ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Homology Directed Repair ◽  
Pathway Choice ◽  
Non Homologous End Joining

DNA double-strand breaks (DSBs) are highly toxic lesions that can be mended via several DNA repair pathways. Multiple factors can influence the choice and the restrictiveness of repair towards a given pathway in order to warrant the maintenance of genome integrity. During V(D)J recombination, RAG-induced DSBs are (almost) exclusively repaired by the non-homologous end-joining (NHEJ) pathway for the benefit of antigen receptor gene diversity. Here, we review the various parameters that constrain repair of RAG-generated DSBs to NHEJ, including the peculiarity of DNA DSB ends generated by the RAG nuclease, the establishment and maintenance of a post-cleavage synaptic complex, and the protection of DNA ends against resection and (micro)homology-directed repair. In this physiological context, we highlight that certain DSBs have limited DNA repair pathway choice options.

scholarly journals FAM35A co-operates with REV7 to coordinate DNA double-strand break repair pathway choice

2018 ◽  
Author(s):  
Steven Findlay ◽  
John Heath ◽  
Vincent M. Luo ◽  
Abba Malina ◽  
Théo Morin ◽  
...  
Keyword(s):  
Dna Repair ◽  
Strand Break ◽  
Dependent Manner ◽  
Repair Pathway ◽  
Dna Double Strand Breaks ◽  
Uncharacterized Protein ◽  
Antibody Diversification ◽  
Pathway Choice ◽  
Dna End Resection ◽  
Non Homologous End Joining

SUMMARYDNA double-strand breaks (DSBs) can be repaired by two major pathways: non-homologous end-joining (NHEJ) and homologous recombination (HR). DNA repair pathway choice is governed by the opposing activities of 53BP1, in complex with its effectors RIF1 and REV7, and BRCA1. However, it remains unknown how the 53BP1/RIF1/REV7 complex stimulates NHEJ and restricts HR to the S/G2 phases of the cell cycle. Using a mass spectrometry (MS)-based approach, we identify 11 high-confidence REV7 interactors and elucidate the role of a previously undescribed factor, FAM35A/SHDL2, as a novel effector of REV7 in the NHEJ pathway. FAM35A depletion impairs NHEJ-mediated DNA repair and compromises antibody diversification by class switch recombination (CSR) in B-cells. FAM35A accumulates at DSBs in a 53BP1-, RIF1- and REV7-dependent manner and antagonizes HR by limiting DNA end resection. In fact, FAM35A is part of a larger complex composed of REV7 and another previously uncharacterized protein, C20orf196/SHDL1, which promotes NHEJ and limits HR. Together, these results establish FAM35A as a novel effector of REV7 in controlling the decision-making process during DSB repair.

scholarly journals RAD6 Promotes Homologous Recombination Repair by Activating the Autophagy-Mediated Degradation of Heterochromatin Protein HP1

2014 ◽  
Vol 35 (2) ◽  
pp. 406-416 ◽  
Author(s):  
Su Chen ◽  
Chen Wang ◽  
Luxi Sun ◽  
Da-Liang Wang ◽  
Lu Chen ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Genome Stability ◽  
Chromosomal Rearrangements ◽  
Strand Break ◽  
Open Chromatin ◽  
Dsb Repair ◽  
Heterochromatin Protein ◽  
Dna Double Strand Break ◽  
Recombination Repair ◽  
Ubiquitin Conjugating Enzyme

Efficient DNA double-strand break (DSB) repair is critical for the maintenance of genome stability. Unrepaired or misrepaired DSBs cause chromosomal rearrangements that can result in severe consequences, such as tumorigenesis. RAD6 is an E2 ubiquitin-conjugating enzyme that plays a pivotal role in repairing UV-induced DNA damage. Here, we present evidence that RAD6 is also required for DNA DSB repair via homologous recombination (HR) by specifically regulating the degradation of heterochromatin protein 1α (HP1α). Our study indicates that RAD6 physically interacts with HP1α and ubiquitinates HP1α at residue K154, thereby promoting HP1α degradation through the autophagy pathway and eventually leading to an open chromatin structure that facilitates efficient HR DSB repair. Furthermore, bioinformatics studies have indicated that the expression of RAD6 and HP1α exhibits an inverse relationship and correlates with the survival rate of patients.

scholarly journals A histone H3K36 chromatin switch coordinates DNA double-strand break repair pathway choice

2014 ◽  
Vol 5 (1) ◽  
Author(s):  
Chen-Chun Pai ◽  
Rachel S. Deegan ◽  
Lakxmi Subramanian ◽  
Csenge Gal ◽  
Sovan Sarkar ◽  
...  
Keyword(s):  
Strand Break ◽  
Double Strand Break ◽  
Double Strand Break Repair ◽  
Repair Pathway ◽  
Dna Double Strand Break ◽  
Pathway Choice ◽  
Break Repair
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