scholarly journals Eukaryotic Translesion Polymerases and Their Roles and Regulation in DNA Damage Tolerance

2009 ◽  
Vol 73 (1) ◽  
pp. 134-154 ◽  
Author(s):  
Lauren S. Waters ◽  
Brenda K. Minesinger ◽  
Mary Ellen Wiltrout ◽  
Sanjay D'Souza ◽  
Rachel V. Woodruff ◽  
...  
Keyword(s):  
Dna Damage ◽  
Damage Tolerance ◽  
Dna Lesions ◽  
Dna Damage Tolerance ◽  
Current State ◽  
Eukaryotic Dna ◽  
A Cell ◽  
Translesion Polymerases ◽  
Stalled Replication Forks

SUMMARY DNA repair and DNA damage tolerance machineries are crucial to overcome the vast array of DNA damage that a cell encounters during its lifetime. In this review, we summarize the current state of knowledge about the eukaryotic DNA damage tolerance pathway translesion synthesis (TLS), a process in which specialized DNA polymerases replicate across from DNA lesions. TLS aids in resistance to DNA damage, presumably by restarting stalled replication forks or filling in gaps that remain in the genome due to the presence of DNA lesions. One consequence of this process is the potential risk of introducing mutations. Given the role of these translesion polymerases in mutagenesis, we discuss the significant regulatory mechanisms that control the five known eukaryotic translesion polymerases: Rev1, Pol ζ, Pol κ, Pol η, and Pol ι.

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 DNA Damage Tolerance by Eukaryotic DNA Polymerase and Primase PrimPol

2017 ◽  
Vol 18 (7) ◽  
pp. 1584 ◽  
Author(s):  
Elizaveta Boldinova ◽  
Paulina Wanrooij ◽  
Evgeniy Shilkin ◽  
Sjoerd Wanrooij ◽  
Alena Makarova
Keyword(s):  
Dna Damage ◽  
Dna Polymerase ◽  
Damage Tolerance ◽  
Dna Damage Tolerance ◽  
Eukaryotic Dna

scholarly journals Participation of the HIM1 gene of yeast Saccharomyces cerevisiae in the error-free branch of post-replicative repair and role Polη in him1-dependent mutagenesis

2020 ◽  
Author(s):  
E. A. Alekseeva ◽  
T. A. Evstyukhina ◽  
V. T. Peshekhonov ◽  
V. G. Korolev
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Dna Damage ◽  
Damage Tolerance ◽  
Dna Damage Tolerance ◽  
Uv Mutagenesis ◽  
Gene Encoding ◽  
Yeast Saccharomyces Cerevisiae ◽  
Recombination Repair ◽  
Repair Pathways

Abstract In eukaryotes, DNA damage tolerance (DDT) is determined by two repair pathways, homologous repair recombination (HRR) and a pathway controlled by the RAD6-epistatic group of genes. Monoubiquitylation of PCNA mediates an error-prone pathway, whereas polyubiquitylation stimulates an error-free pathway. The error-free pathway involves components of recombination repair; however, the factors that act in this pathway remain largely unknown. Here, we report that the HIM1 gene participates in error-free DDT. Notably, inactivation RAD30 gene encoding Polη completely suppresses him1-dependent UV mutagenesis. Furthermore, data obtained show a significant role of Polη in him1-dependent mutagenesis, especially at non-bipyrimidine sites (NBP sites). We demonstrate that him1 mutation significantly reduces the efficiency of the induction expression of RNR genes after UV irradiation. Besides, this paper presents evidence that significant increase in the dNTP levels suppress him1-dependent mutagenesis. Our findings show that Polη responsible for him1-dependent mutagenesis.

scholarly journals DNA damage tolerance in hematopoietic stem and progenitor cells in mice

2017 ◽  
Vol 114 (33) ◽  
pp. E6875-E6883 ◽  
Author(s):  
Bas Pilzecker ◽  
Olimpia Alessandra Buoninfante ◽  
Paul van den Berk ◽  
Cesare Lancini ◽  
Ji-Ying Song ◽  
...  
Keyword(s):  
Dna Damage ◽  
Progenitor Cells ◽  
Damage Tolerance ◽  
Premature Aging ◽  
Intrinsic Defect ◽  
Dna Damage Tolerance ◽  
Erythroid Progenitor ◽  
Hematopoietic Stem ◽  
Fork Stalling

DNA damage tolerance (DDT) enables bypassing of DNA lesions during replication, thereby preventing fork stalling, replication stress, and secondary DNA damage related to fork stalling. Three modes of DDT have been documented: translesion synthesis (TLS), template switching (TS), and repriming. TLS and TS depend on site-specific PCNA K164 monoubiquitination and polyubiquitination, respectively. To investigate the role of DDT in maintaining hematopoietic stem cells (HSCs) and progenitors, we used PcnaK164R/K164R mice as a unique DDT-defective mouse model. Analysis of the composition of HSCs and HSC-derived multipotent progenitors (MPPs) revealed a significantly reduced number of HSCs, likely owing to increased differentiation of HSCs toward myeloid/erythroid-associated MPP2s. This skewing came at the expense of the number of lymphoid-primed MPP4s, which appeared to be compensated for by increased MPP4 proliferation. Furthermore, defective DDT decreased the numbers of MPP-derived common lymphoid progenitor (CLP), common myeloid progenitor (CMP), megakaryocyte-erythroid progenitor (MEP), and granulocyte-macrophage progenitor (GMP) cells, accompanied by increased cell cycle arrest in CMPs. The HSC and MPP phenotypes are reminiscent of premature aging and stressed hematopoiesis, and indeed progressed with age and were exacerbated on cisplatin exposure. Bone marrow transplantations revealed a strong cell intrinsic defect of DDT-deficient HSCs in reconstituting lethally irradiated mice and a strong competitive disadvantage when cotransplanted with wild-type HSCs. These findings indicate a critical role of DDT in maintaining HSCs and progenitor cells, and in preventing premature aging.

Role of yeast Rad5 and its human orthologs, HLTF and SHPRH in DNA damage tolerance

DNA Repair ◽  
2010 ◽  
Vol 9 (3) ◽  
pp. 257-267 ◽  
Author(s):  
Ildiko Unk ◽  
Ildikó Hajdú ◽  
András Blastyák ◽  
Lajos Haracska
Keyword(s):  
Dna Damage ◽  
Damage Tolerance ◽  
Dna Damage Tolerance ◽  
Human Orthologs

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 PCNA Ubiquitylation: Instructive or Permissive to DNA Damage Tolerance Pathways?

Biomolecules ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1543
Author(s):  
Jun Che ◽  
Xin Hong ◽  
Hai Rao
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Damage Tolerance ◽  
Translesion Synthesis ◽  
Dna Lesions ◽  
Template Switching ◽  
Dna Damage Tolerance ◽  
Future Studies ◽  
Dna Lesion ◽  
Replicative Polymerases

DNA lesions escaping from repair often block the DNA replicative polymerases required for DNA replication and are handled during the S/G2 phases by the DNA damage tolerance (DDT) mechanisms, which include the error-prone translesion synthesis (TLS) and the error-free template switching (TS) pathways. Where the mono-ubiquitylation of PCNA K164 is critical for TLS, the poly-ubiquitylation of the same residue is obligatory for TS. However, it is not known how cells divide the labor between TLS and TS. Due to the fact that the type of DNA lesion significantly influences the TLS and TS choice, we propose that, instead of altering the ratio between the mono- and poly-Ub forms of PCNA, the competition between TLS and TS would automatically determine the selection between the two pathways. Future studies, especially the single integrated lesion “i-Damage” system, would elucidate detailed mechanisms governing the choices of specific DDT pathways.

scholarly journals Replication intermediate architecture reveals the chronology of DNA damage tolerance pathways at UV-stalled replication forks in human cells

2020 ◽  
Author(s):  
Yann Benureau ◽  
Caroline Pouvelle ◽  
Eliana Moreira Tavares ◽  
Pauline Dupaigne ◽  
Emmanuelle Despras ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Synthesis ◽  
Replication Fork ◽  
Damage Tolerance ◽  
Dna Lesions ◽  
Human Cells ◽  
Compensatory Mechanism ◽  
Dna Damage Tolerance ◽  
Replication Intermediate

AbstractDNA lesions in S phase threaten genome stability. The DNA damage tolerance (DDT) pathways overcome these obstacles and allow completion of DNA synthesis by the use of specialised translesion (TLS) DNA polymerases or through recombination-related processes. However, how these mechanisms coordinate with each other and with bulk replication remain elusive. To address these issues, we monitored the variation of replication intermediate architecture in response to ultraviolet irradiation using transmission electron microscopy. We show that the TLS polymerase η, able to accurately bypass the major UV lesion and mutated in the skin cancer-prone xeroderma pigmentosum variant (XPV) syndrome, acts at the replication fork to resolve uncoupling and prevent post-replicative gap accumulation. Repriming occurs as a compensatory mechanism when this on-the-fly mechanism cannot operate, and is therefore predominant in XPV cells. Interestingly, our data support a recombination-independent function of RAD51 at the replication fork to sustain repriming. Finally, we provide evidence for the post-replicative commitment of recombination in gap repair and for pioneering observations of in vivo recombination intermediates. Altogether, we propose a chronology of UV damage tolerance in human cells that highlights the key role of polη in shaping this response and ensuring the continuity of DNA synthesis.

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