Conservation of DNA damage tolerance pathways from yeast to humans

2007 ◽  
Vol 35 (5) ◽  
pp. 1334-1337 ◽  
Author(s):  
H.D. Ulrich
Keyword(s):  
Damage Tolerance ◽  
Reference Model ◽  
Current Knowledge ◽  
Dna Lesions ◽  
Nuclear Antigen ◽  
Lesion Bypass ◽  
Dna Damage Tolerance ◽  
Experimental Systems ◽  
Species Specific ◽  
Enzymatic Machinery

Damage tolerance mechanisms, which allow the bypass of DNA lesions during replication, are controlled in eukaryotic cells by mono- and poly-ubiquitination of the DNA polymerase cofactor PCNA (proliferating-cell nuclear antigen). In the present review, I will summarize our current knowledge of the enzymatic machinery for ubiquitination of PCNA and the way in which the modifications affect PCNA function during replication and lesion bypass in different organisms. Using the budding yeast as a reference model, I will highlight some of the species-specific differences, but also point out the common principles that emerge from the genetic and biochemical studies of damage tolerance in a range of experimental systems.

scholarly journals DNA damage-specific deubiquitination regulates Rad18 functions to suppress mutagenesis

2014 ◽  
Vol 206 (2) ◽  
pp. 183-197 ◽  
Author(s):  
Michelle K. Zeman ◽  
Jia-Ren Lin ◽  
Raimundo Freire ◽  
Karlene A. Cimprich
Keyword(s):  
Dna Damage ◽  
Dna Lesions ◽  
Nuclear Antigen ◽  
Lesion Bypass ◽  
Dna Damage Tolerance ◽  
E3 Ligases ◽  
Plant Homeodomain ◽  
In Trans ◽  
Fork Stalling ◽  
Proliferating Cell

Deoxyribonucleic acid (DNA) lesions encountered during replication are often bypassed using DNA damage tolerance (DDT) pathways to avoid prolonged fork stalling and allow for completion of DNA replication. Rad18 is a central E3 ubiquitin ligase in DDT, which exists in a monoubiquitinated (Rad18•Ub) and nonubiquitinated form in human cells. We find that Rad18 is deubiquitinated when cells are treated with methyl methanesulfonate or hydrogen peroxide. The ubiquitinated form of Rad18 does not interact with SNF2 histone linker plant homeodomain RING helicase (SHPRH) or helicase-like transcription factor, two downstream E3 ligases needed to carry out error-free bypass of DNA lesions. Instead, it interacts preferentially with the zinc finger domain of another, nonubiquitinated Rad18 and may inhibit Rad18 function in trans. Ubiquitination also prevents Rad18 from localizing to sites of DNA damage, inducing proliferating cell nuclear antigen monoubiquitination, and suppressing mutagenesis. These data reveal a new role for monoubiquitination in controlling Rad18 function and suggest that damage-specific deubiquitination promotes a switch from Rad18•Ub–Rad18 complexes to the Rad18–SHPRH complexes necessary for error-free lesion bypass in cells.

scholarly journals Helicase-Like Transcription Factor HLTF and E3 Ubiquitin Ligase SHPRH Confer DNA Damage Tolerance through Direct Interactions with Proliferating Cell Nuclear Antigen (PCNA)

2020 ◽  
Vol 21 (3) ◽  
pp. 693 ◽  
Author(s):  
Mareike Seelinger ◽  
Marit Otterlei
Keyword(s):  
Dna Damage ◽  
Transcription Factor ◽  
Damage Tolerance ◽  
Genome Instability ◽  
Ring Finger ◽  
Nuclear Antigen ◽  
Common Mutation ◽  
Dna Damage Tolerance ◽  
Replicative Stress ◽  
Template Switch

To prevent replication fork collapse and genome instability under replicative stress, DNA damage tolerance (DDT) mechanisms have evolved. The RAD5 homologs, HLTF (helicase-like transcription factor) and SHPRH (SNF2, histone-linker, PHD and RING finger domain-containing helicase), both ubiquitin ligases, are involved in several DDT mechanisms; DNA translesion synthesis (TLS), fork reversal/remodeling and template switch (TS). Here we show that these two human RAD5 homologs contain functional APIM PCNA interacting motifs. Our results show that both the role of HLTF in TLS in HLTF overexpressing cells, and nuclear localization of SHPRH, are dependent on interaction of HLTF and SHPRH with PCNA. Additionally, we detected multiple changes in the mutation spectra when APIM in overexpressed HLTF or SHPRH were mutated compared to overexpressed wild type proteins. In plasmids from cells overexpressing the APIM mutant version of HLTF, we observed a decrease in C to T transitions, the most common mutation caused by UV irradiation, and an increase in mutations on the transcribed strand. These results strongly suggest that direct binding of HLTF and SHPRH to PCNA is vital for their function in DDT.

scholarly journals Multisite SUMOylation restrains DNA polymerase η interactions with DNA damage sites

2020 ◽  
Vol 295 (25) ◽  
pp. 8350-8362 ◽  
Author(s):  
Claire Guérillon ◽  
Stine Smedegaard ◽  
Ivo A. Hendriks ◽  
Michael L. Nielsen ◽  
Niels Mailand
Keyword(s):  
Dna Damage ◽  
Dna Polymerase ◽  
Feedback Inhibition ◽  
Dna Lesions ◽  
Nuclear Antigen ◽  
Inhibition Mechanism ◽  
Proteomic Profiling ◽  
Lesion Bypass ◽  
Y Family ◽  
Damaged Dna

Translesion DNA synthesis (TLS) mediated by low-fidelity DNA polymerases is an essential cellular mechanism for bypassing DNA lesions that obstruct DNA replication progression. However, the access of TLS polymerases to the replication machinery must be kept tightly in check to avoid excessive mutagenesis. Recruitment of DNA polymerase η (Pol η) and other Y-family TLS polymerases to damaged DNA relies on proliferating cell nuclear antigen (PCNA) monoubiquitylation and is regulated at several levels. Using a microscopy-based RNAi screen, here we identified an important role of the SUMO modification pathway in limiting Pol η interactions with DNA damage sites in human cells. We found that Pol η undergoes DNA damage- and protein inhibitor of activated STAT 1 (PIAS1)-dependent polySUMOylation upon its association with monoubiquitylated PCNA, rendering it susceptible to extraction from DNA damage sites by SUMO-targeted ubiquitin ligase (STUbL) activity. Using proteomic profiling, we demonstrate that Pol η is targeted for multisite SUMOylation, and that collectively these SUMO modifications are essential for PIAS1- and STUbL-mediated displacement of Pol η from DNA damage sites. These findings suggest that a SUMO-driven feedback inhibition mechanism is an intrinsic feature of TLS-mediated lesion bypass functioning to curtail the interaction of Pol η with PCNA at damaged DNA to prevent harmful mutagenesis.

scholarly journals Elevated Hedgehog activity contributes to attenuated DNA damage responses in aged hematopoietic cells

Leukemia ◽  
2019 ◽  
Vol 34 (4) ◽  
pp. 1125-1134
Author(s):  
Annika Scheffold ◽  
Ali H. Baig ◽  
Zhiyang Chen ◽  
Sarah E. von Löhneysen ◽  
Friedrich Becker ◽  
...  
Keyword(s):  
Dna Damage ◽  
Therapeutic Strategy ◽  
Damage Tolerance ◽  
Dna Lesions ◽  
Hematopoietic Progenitors ◽  
Dna Damage Tolerance ◽  
Hematopoietic System ◽  
Dna Damage Responses ◽  
Underlying Mechanisms ◽  
Bulky Dna Lesions

AbstractAccumulation of DNA damage and myeloid-skewed differentiation characterize aging of the hematopoietic system, yet underlying mechanisms remain incompletely understood. Here, we show that aging hematopoietic progenitor cells particularly of the myeloid branch exhibit enhanced resistance to bulky DNA lesions—a relevant type of DNA damage induced by toxins such as cancer drugs or endogenous aldehydes. We identified aging-associated activation of the Hedgehog (Hh) pathway to be connected to this phenotype. Inhibition of Hh signaling reverts DNA damage tolerance and DNA damage-resistant proliferation in aged hematopoietic progenitors. Vice versa, elevating Hh activity in young hematopoietic progenitors is sufficient to impair DNA damage responses. Altogether, these findings provide experimental evidence for aging-associated increases in Hh activity driving DNA damage tolerance in myeloid progenitors and myeloid-skewed differentiation. Modulation of Hh activity could thus be explored as a therapeutic strategy to prevent DNA damage tolerance, myeloid skewing, and disease development in the aging hematopoietic system.

scholarly journals Monoubiquitylation of histone H2B contributes to the bypass of DNA damage during and after DNA replication

2017 ◽  
Vol 114 (11) ◽  
pp. E2205-E2214 ◽  
Author(s):  
Shih-Hsun Hung ◽  
Ronald P. Wong ◽  
Helle D. Ulrich ◽  
Cheng-Fu Kao
Keyword(s):  
Dna Damage ◽  
Replication Fork ◽  
Dna Lesions ◽  
Template Switching ◽  
Lesion Bypass ◽  
Dna Damage Tolerance ◽  
Cytological Evidence ◽  
Histone H2b ◽  
Chromatin Dynamics ◽  
Dna Lesion

DNA lesion bypass is mediated by DNA damage tolerance (DDT) pathways and homologous recombination (HR). The DDT pathways, which involve translesion synthesis and template switching (TS), are activated by the ubiquitylation (ub) of PCNA through components of the RAD6-RAD18 pathway, whereas the HR pathway is independent of RAD18. However, it is unclear how these processes are coordinated within the context of chromatin. Here we show that Bre1, an ubiquitin ligase specific for histone H2B, is recruited to chromatin in a manner coupled to replication of damaged DNA. In the absence of Bre1 or H2Bub, cells exhibit accumulation of unrepaired DNA lesions. Consequently, the damaged forks become unstable and resistant to repair. We provide physical, genetic, and cytological evidence that H2Bub contributes toward both Rad18-dependent TS and replication fork repair by HR. Using an inducible system of DNA damage bypass, we further show that H2Bub is required for the regulation of DDT after genome duplication. We propose that Bre1-H2Bub facilitates fork recovery and gap-filling repair by controlling chromatin dynamics in response to replicative DNA damage.

scholarly journals Functional and Physical Interaction of Yeast Mgs1 with PCNA: Impact on RAD6-Dependent DNA Damage Tolerance

2006 ◽  
Vol 26 (14) ◽  
pp. 5509-5517 ◽  
Author(s):  
Takashi Hishida ◽  
Tomoko Ohya ◽  
Yoshino Kubota ◽  
Yusuke Kamada ◽  
Hideo Shinagawa
Keyword(s):  
Dna Damage ◽  
Posttranslational Modifications ◽  
Cell Cycle Progression ◽  
Damage Tolerance ◽  
Genome Instability ◽  
Dna Helicase ◽  
Nuclear Antigen ◽  
Physical Interaction ◽  
Dna Damage Tolerance ◽  
Exogenous Dna

ABSTRACT Proliferating cell nuclear antigen (PCNA), a sliding clamp required for processive DNA synthesis, provides attachment sites for various other proteins that function in DNA replication, DNA repair, cell cycle progression and chromatin assembly. It has been shown that differential posttranslational modifications of PCNA by ubiquitin or SUMO play a pivotal role in controlling the choice of pathway for rescuing stalled replication forks. Here, we explored the roles of Mgs1 and PCNA in replication fork rescue. We provide evidence that Mgs1 physically associates with PCNA and that Mgs1 helps suppress the RAD6 DNA damage tolerance pathway in the absence of exogenous DNA damage. We also show that PCNA sumoylation inhibits the growth of mgs1 rad18 double mutants, in which PCNA sumoylation and the Srs2 DNA helicase coordinately prevent RAD52-dependent homologous recombination. The proposed roles for Mgs1, Srs2, and modified PCNA during replication arrest highlight the importance of modulating the RAD6 and RAD52 pathways to avoid genome instability.

scholarly journals Non-Recombinogenic Functions of Rad51, BRCA2, and Rad52 in DNA Damage Tolerance

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1550
Author(s):  
Félix Prado
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Damage Tolerance ◽  
Molecular Switches ◽  
Strand Exchange ◽  
Template Switching ◽  
Replication Forks ◽  
Lesion Bypass ◽  
Dna Damage Tolerance ◽  
Exchange Activity

The DNA damage tolerance (DDT) response is aimed to timely and safely complete DNA replication by facilitating the advance of replication forks through blocking lesions. This process is associated with an accumulation of single-strand DNA (ssDNA), both at the fork and behind the fork. Lesion bypass and ssDNA filling can be performed by translation synthesis (TLS) and template switching mechanisms. TLS uses low-fidelity polymerases to incorporate a dNTP opposite the blocking lesion, whereas template switching uses a Rad51/ssDNA nucleofilament and the sister chromatid to bypass the lesion. Rad51 is loaded at this nucleofilament by two mediator proteins, BRCA2 and Rad52, and these three factors are critical for homologous recombination (HR). Here, we review recent advances showing that Rad51, BRCA2, and Rad52 perform some of these functions through mechanisms that do not require the strand exchange activity of Rad51: the formation and protection of reversed fork structures aimed to bypass blocking lesions, and the promotion of TLS. These findings point to the central HR proteins as potential molecular switches in the choice of the mechanism of DDT.

scholarly journals DNA damage tolerance in stem cells, ageing, mutagenesis, disease and cancer therapy

2019 ◽  
Vol 47 (14) ◽  
pp. 7163-7181 ◽  
Author(s):  
Bas Pilzecker ◽  
Olimpia Alessandra Buoninfante ◽  
Heinz Jacobs
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Damage Tolerance ◽  
Essential Feature ◽  
Dna Lesions ◽  
Template Switching ◽  
Dna Damage Tolerance ◽  
Response Network ◽  
Damage Response ◽  
Fork Stalling

AbstractThe DNA damage response network guards the stability of the genome from a plethora of exogenous and endogenous insults. An essential feature of the DNA damage response network is its capacity to tolerate DNA damage and structural impediments during DNA synthesis. This capacity, referred to as DNA damage tolerance (DDT), contributes to replication fork progression and stability in the presence of blocking structures or DNA lesions. Defective DDT can lead to a prolonged fork arrest and eventually cumulate in a fork collapse that involves the formation of DNA double strand breaks. Four principal modes of DDT have been distinguished: translesion synthesis, fork reversal, template switching and repriming. All DDT modes warrant continuation of replication through bypassing the fork stalling impediment or repriming downstream of the impediment in combination with filling of the single-stranded DNA gaps. In this way, DDT prevents secondary DNA damage and critically contributes to genome stability and cellular fitness. DDT plays a key role in mutagenesis, stem cell maintenance, ageing and the prevention of cancer. This review provides an overview of the role of DDT in these aspects.

scholarly journals Mechanisms of DNA Damage Tolerance: Post-Translational Regulation of PCNA

Genes ◽  
2018 ◽  
Vol 10 (1) ◽  
pp. 10 ◽  
Author(s):  
Wendy Leung ◽  
Ryan Baxley ◽  
George-Lucian Moldovan ◽  
Anja-Katrin Bielinsky
Keyword(s):  
Dna Damage ◽  
Translational Regulation ◽  
Damage Tolerance ◽  
Somatic Hypermutation ◽  
Critical Role ◽  
Nuclear Antigen ◽  
Template Switching ◽  
Dna Damage Tolerance ◽  
Class Switch ◽  
Dna Lesion

DNA damage is a constant source of stress challenging genomic integrity. To ensure faithful duplication of our genomes, mechanisms have evolved to deal with damage encountered during replication. One such mechanism is referred to as DNA damage tolerance (DDT). DDT allows for replication to continue in the presence of a DNA lesion by promoting damage bypass. Two major DDT pathways exist: error-prone translesion synthesis (TLS) and error-free template switching (TS). TLS recruits low-fidelity DNA polymerases to directly replicate across the damaged template, whereas TS uses the nascent sister chromatid as a template for bypass. Both pathways must be tightly controlled to prevent the accumulation of mutations that can occur from the dysregulation of DDT proteins. A key regulator of error-prone versus error-free DDT is the replication clamp, proliferating cell nuclear antigen (PCNA). Post-translational modifications (PTMs) of PCNA, mainly by ubiquitin and SUMO (small ubiquitin-like modifier), play a critical role in DDT. In this review, we will discuss the different types of PTMs of PCNA and how they regulate DDT in response to replication stress. We will also cover the roles of PCNA PTMs in lagging strand synthesis, meiotic recombination, as well as somatic hypermutation and class switch recombination.

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