Diepoxybutane interstrand cross-links induce DNA bending

Millard, Julie T.; McGowan, Erin E.; Bradley, Sharonda Q.

doi:10.1016/j.biochi.2011.07.030

Cited by 7 publications

(3 citation statements)

References 30 publications

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“…The bridge formed only contains four carbon atoms, which has been hypothesized to produce a major distortion on DNA. Through gel retardation experiments, it has been shown to lead to a bending of around 34° towards the major groove [ 26 ].…”

Section: Origin Of Iclsmentioning

confidence: 99%

Cellular response to DNA interstrand crosslinks: the Fanconi anemia pathway

Martínez

Liang

Cohn

2016

Cell. Mol. Life Sci.

108

114

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Interstrand crosslinks (ICLs) are a highly toxic form of DNA damage. ICLs can interfere with vital biological processes requiring separation of the two DNA strands, such as replication and transcription. If ICLs are left unrepaired, it can lead to mutations, chromosome breakage and mitotic catastrophe. The Fanconi anemia (FA) pathway can repair this type of DNA lesion, ensuring genomic stability. In this review, we will provide an overview of the cellular response to ICLs. First, we will discuss the origin of ICLs, comparing various endogenous and exogenous sources. Second, we will describe FA proteins as well as FA-related proteins involved in ICL repair, and the post-translational modifications that regulate these proteins. Finally, we will review the process of how ICLs are repaired by both replication-dependent and replication-independent mechanisms.

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Section: Origin Of Iclsmentioning

confidence: 99%

Cellular response to DNA interstrand crosslinks: the Fanconi anemia pathway

Martínez

Liang

Cohn

2016

Cell. Mol. Life Sci.

108

114

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“…These perturbations typically result in single-stranded DNA breaks, the rate of formation of which might differ between the two alkylating agents, resulting in the observed differences. Specifically, ICLs produced by DEB result in substantial DNA helix distortion to the magnitude of ~34° per lesion towards the major groove [64] while those produced by MMC are minimal [65]. The extent of helical distortion has been shown to influence the efficiency of nuclease activity near ICLs, with the less-distorting lesions showing a ~3-fold lower incision frequency [66].…”

Section: Discussionmentioning

confidence: 99%

EXD2 and WRN exonucleases are required for interstrand crosslink repair in Drosophila

Chennuri

Cox

Saunders

2018

Preprint

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Interstrand crosslinks (ICLs) present a major threat to genome integrity, preventing both the correct transcription of active chromatin and complete replication of the genome. This is exploited in genotoxic chemotherapy where ICL induction is used to kill highly proliferative cancer cells.Repair of ICLs involves a complex interplay of numerous proteins, including those in the Fanconi anemia (FA) pathway, though alternative and parallel pathways have been postulated. Here, we investigate the role of the 3'-5' exonuclease, EXD2, and the highly related WRN exonuclease (implicated in premature ageing human Werner syndrome), in repair of interstrand crosslinks in the fruit fly, Drosophila melanogaster. We find that flies mutant for EXD2 (DmEXD2) have elevated rates of genomic instability resulting from chromosome breakage and loss of the resulting acentric fragments, in contrast to WRN exonuclease (DmWRNexo) mutants where excess homologous recombination is the principal mechanism of genomic instability. Most notably, we demonstrate that proliferating larval neuroblasts mutant for either DmWRNexo or DmEXD2 are deficient in repair of DNA interstrand crosslinks caused by diepoxybutane or mitomycin C, strongly suggesting that each nuclease individually plays a role in repair of ICLs in flies. These findings have significant implications not only for understanding the complex process of ICL repair in humans, but also for enhancing cancer therapies that rely on ICL induction, with caveats for cancer therapy in Werner syndrome and Fanconi anemia patients.

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“…We focused specifically on mutants defective in HR core components and FR factors, but chose not to examine mutants in substrate preparation and intermediate processing, or in DNA-damage signaling. For experimental purposes, we took resistance to chronic exposure to FA as a measure of DPC repair proficiency and resistance to DEB as a measure of ICL repair, although with the caveat that the specificity of both these agents is by no means strictly confined to these types of lesions (McGhee and von Hippel 1975;Michaelson-Richie et al 2010;Millard et al 2012;Hoffman et al 2015). Both are highly reactive chemicals with broad specificities and with overlap in their respective capabilities in cross-link formation.…”

Section: Contribution Of Hr Components To Repair Of Dpcsmentioning

confidence: 99%

Loss of Cohesin Subunit Rec8 Switches Rad51 Mediator Dependence in Resistance to Formaldehyde Toxicity in Ustilago maydis

Sutherland¹,

Holloman

2018

Genetics

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DNA-protein cross-links (DPCs) are frequently occurring lesions that provoke continual threats to the integrity of the genome by interference with replication and transcription. Reactive aldehydes generated from endogenous metabolic processes or produced in the environment are sources that trigger cross-linking of DNA with associated proteins. DNA repair pathways in place for removing DPCs, or for bypassing them to enable completion of replication, include homologous recombination (HR) and replication fork remodeling (FR) systems. Here, we surveyed a set of mutants defective in known HR and FR components to determine their contribution toward maintaining resistance to chronic formaldehyde (FA) exposure in Ustilago maydis, a fungus that relies on the BRCA2-family member Brh2 as the principal Rad51 mediator in repair of DNA strand breaks. We found that, in addition to Brh2, Rad52 was also vital for resistance to FA. Deleting the gene for Rec8, a kleisin subunit of cohesin, eliminated the requirement for Brh2, but not Rad52, in FA resistance. The Rad51 K133R mutant variant that is able to bind DNA but unable to dissociate from it was able to support resistance to FA. These findings suggest a model for DPC repair and tolerance that features a specialized role for Rad52, enabling Rad51 to access DNA in its noncanonical capacity of replication fork protection rather than DNA strand transfer.

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Diepoxybutane interstrand cross-links induce DNA bending

Cited by 7 publications

References 30 publications

Cellular response to DNA interstrand crosslinks: the Fanconi anemia pathway

Cellular response to DNA interstrand crosslinks: the Fanconi anemia pathway

EXD2 and WRN exonucleases are required for interstrand crosslink repair in Drosophila

Loss of Cohesin Subunit Rec8 Switches Rad51 Mediator Dependence in Resistance to Formaldehyde Toxicity in Ustilago maydis

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