How to fix DNA-protein crosslinks

Kühbacher, Ulrike; Duxin, Julien P.

doi:10.1016/j.dnarep.2020.102924

Cited by 35 publications

(29 citation statements)

References 153 publications

(224 reference statements)

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“… Stingele et al (2017) have proposed that each constituent of DPC: DNA, protein, and the covalent linkage between them might be processed by three different repair mechanisms. A recent paper by Kühbacher and Duxin (2020) provides comprehensive review on the formation and repair of DPCs. In this review, we summarize the current knowledge regarding the repair mechanisms involved in removal of DHCs induced by various genotoxic agents.…”

Section: Introductionmentioning

confidence: 99%

DNA-Histone Cross-Links: Formation and Repair

Pachva¹,

Kisselev

Matkarimov

et al. 2020

Front. Cell Dev. Biol.

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The nucleosome is a stretch of DNA wrapped around a histone octamer. Electrostatic interactions and hydrogen bonds between histones and DNA are vital for the stable organization of nucleosome core particles, and for the folding of chromatin into more compact structures, which regulate gene expression via controlled access to DNA. As a drawback of tight association, under genotoxic stress, DNA can accidentally cross-link to histone in a covalent manner, generating a highly toxic DNA-histone cross-link (DHC). DHC is a bulky lesion that can impede DNA transcription, replication, and repair, often with lethal consequences. The chemotherapeutic agent cisplatin, as well as ionizing and ultraviolet irradiations and endogenously occurring reactive aldehydes, generate DHCs by forming either stable or transient covalent bonds between DNA and side-chain amino groups of histone lysine residues. The mechanisms of DHC repair start to unravel, and certain common principles of DNA-protein cross-link (DPC) repair mechanisms that participate in the removal of cross-linked histones from DNA have been described. In general, DPC is removed via a two-step repair mechanism. First, cross-linked proteins are degraded by specific DPC proteases or by the proteasome, relieving steric hindrance. Second, the remaining DNA-peptide cross-links are eliminated in various DNA repair pathways. Delineating the molecular mechanisms of DHC repair would help target specific DNA repair proteins for therapeutic intervention to combat tumor resistance to chemotherapy and radiotherapy.

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Section: Introductionmentioning

confidence: 99%

DNA-Histone Cross-Links: Formation and Repair

Pachva¹,

Kisselev

Matkarimov

et al. 2020

Front. Cell Dev. Biol.

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“…Repair mechanisms can target different components of a DNA–protein cross-link ( i.e. , the DNA molecule, the cross-link bond, or protein) and may depend on the stage of the cell cycle ( 27 , 28 , 36 ). Most DNA–protein cross-links are too large for DNA polymerase bypass ( 37 ), and proteases are believed to cleave the proteins to smaller peptides that can be repaired by nucleotide excision repair (NER) ( 38 ) or homologous recombination (HR) or bypassed by translesion synthesis (TLS) polymerases ( 39 ).…”

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confidence: 99%

Enzymatic bypass of an N6-deoxyadenosine DNA–ethylene dibromide–peptide cross-link by translesion DNA polymerases

Ghodke¹,

Gonzalez-Vasquez²,

Wang

et al. 2021

Journal of Biological Chemistry

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Unrepaired DNA–protein cross-links, due to their bulky nature, can stall replication forks and result in genome instability. Large DNA–protein cross-links can be cleaved into DNA–peptide cross-links, but the extent to which these smaller fragments disrupt normal replication is not clear. Ethylene dibromide (1,2-dibromoethane) is a known carcinogen that can cross-link the repair protein O 6 -alkylguanine-DNA alkyltransferase (AGT) to the N6 position of deoxyadenosine (dA) in DNA, as well as four other positions in DNA. We investigated the effect of a 15-mer peptide from the active site of AGT, cross-linked to the N6 position of dA, on DNA replication by human translesion synthesis DNA polymerases (Pols) η, ⍳, and κ. The peptide–DNA cross-link was bypassed by the three polymerases at different rates. In steady-state kinetics, the specificity constant ( k cat / K m ) for incorporation of the correct nucleotide opposite to the adduct decreased by 220-fold with Pol κ, tenfold with pol η, and not at all with Pol ⍳. Pol η incorporated all four nucleotides across from the lesion, with the preference dT > dC > dA > dG, while Pol ⍳ and κ only incorporated the correct nucleotide. However, LC-MS/MS analysis of the primer-template extension product revealed error-free bypass of the cross-linked 15-mer peptide by Pol η. We conclude that a bulky 15-mer peptide cross-linked to the N6 position of dA can retard polymerization and cause miscoding but that overall fidelity is not compromised because only correct pairs are extended.

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“…Reverses SPRTN monoubiquitylation to promote its chromatin access [65] Trends in Cell Biology OPEN ACCESS domain (SPRTN) and the proteasome, offers an important means of recognizing and resolving this bulky and highly heterogenous class of DNA lesion [12]. While the CMG is ultimately able to bypass DPCs on the leading strand in a manner that requires the helicase regulator of telomere length 1 (RTEL1) [60], it temporally stalls at these lesions, triggering DPC ubiquitylation by the replisome-associated ubiquitin ligase TRAF-interacting protein (TRAIP), which appears to promiscuously ubiquitylate proteins ahead of the CMG [61].…”

Section: Vcpip1mentioning

confidence: 99%

“…Specifically, it was recently shown that the fork-associated protein HMCES forms DPCs at abasic sites to prevent their error-prone processing, with HMCES protein adducts being subsequently resolved via ubiquitin-dependent proteolysis [67]. Outside the context of DNA replication, when DPCs cannot be resolved via the replisome, SUMOylation is indispensable for DPC removal in a manner that may involve downstream processing of the adducted protein via ubiquitylation and the proteasome [12,68,69].…”

Section: Vcpip1mentioning

confidence: 99%

“…including mainstay chemotherapeutic drugs that drain essential DNA replication resources such as dNTP pools or generate replication fork barriers in the form of challenging DNA lesions [e.g., DNA interstrand crosslinks (ICLs) and DNA-protein crosslinks (DPCs)], may necessitate more extensive remodeling of replication fork structure and composition [10][11][12] (Figure 1A-C). Accordingly, cells employ sophisticated rescue mechanisms for dealing with the threats posed by a diverse range of genotoxic insults encountered by replication forks.…”

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confidence: 99%

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Ubiquitylation at Stressed Replication Forks: Mechanisms and Functions

Mirsanaye

Typas

Mailand

2021

Trends in Cell Biology

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Accurate duplication of chromosomal DNA is vital for faithful transmission of the genome during cell division. However, DNA replication integrity is frequently challenged by genotoxic insults that compromise the progression and stability of replication forks, posing a threat to genome stability. It is becoming clear that the organization of the replisome displays remarkable flexibility in responding to and overcoming a wide spectrum of fork-stalling insults, and that these transactions are dynamically orchestrated and regulated by protein post-translational modifications (PTMs) including ubiquitylation. In this review, we highlight and discuss important recent advances on how ubiquitin-mediated signaling at the replication fork plays a crucial multifaceted role in regulating replisome composition and remodeling its configuration upon replication stress, thereby ensuring high-fidelity duplication of the genome. Replication Stress and Ubiquitin SignalingPrecise and complete replication of cellular DNA during the S phase of each cell cycle is essential for genome stability, cell proliferation, and organismal fitness. The DNA replication process commences prior to S phase, when replication origins are licensed by the loading of inactive double minichromosome maintenance complex (MCM)2-7 hexamers [1-3]. In S phase, origin firing converts these double hexamers into active, bidirectional replication forks, through the recruitment of CDC45 and the GINS complex, leading to formation of the replicative CDC45-MCM2-7-GINS (CMG) helicase that translocates on the leading strand to unwind the duplex DNA template [4,5]. Although eukaryotic DNA replication initiates from multiple replication origins, only a fraction of licensed origins fire during a normal S phase. However, when obstacles that hinder replication fork progression are encountered, activation of otherwise dormant nearby origins provides an important rescue mechanism for completing genome duplication [6]. In S phase, the active replisome, consisting of the CMG helicase, replicative DNA polymerases, the replication factor C (RFC)-loaded clamp proliferating cell nuclear antigen (PCNA), and auxiliary factors, regulates every aspect of bidirectional replication, which occurs continuously on the leading strand and discontinuously on the lagging strand [7].Deregulation of DNA replication, giving rise to replication stress (see Glossary), is a hallmark of cancer cells and a recognized driver of genomic instability [8-10], representing an attractive target for clinical intervention. However, given the sheer size and complex organization of vertebrate genomes, low levels of replication stress occur naturally in most proliferating cells, arising due to obstacles including heterochromatin-imposed barriers (e.g., repetitive DNA sequences and G4 quadruplexes), replication-transcription collisions, ribonucleotide misincorporation, modified or mismatched nucleotides, and helix-distorting adducts that stall the advancing replication machinery [10]. Under normal conditions, such impe...

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How to fix DNA-protein crosslinks

Cited by 35 publications

References 153 publications

DNA-Histone Cross-Links: Formation and Repair

DNA-Histone Cross-Links: Formation and Repair

Enzymatic bypass of an N6-deoxyadenosine DNA–ethylene dibromide–peptide cross-link by translesion DNA polymerases

Ubiquitylation at Stressed Replication Forks: Mechanisms and Functions

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