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 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.

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 The Human RAD5 Homologs, HLTF and SHPRH, Have Separate Functions in DNA Damage Tolerance Dependent on the DNA Lesion Type

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 463
Author(s):  
Mareike Seelinger ◽  
Caroline Krogh Søgaard ◽  
Marit Otterlei
Keyword(s):  
Dna Damage ◽  
Cell Line ◽  
Cell Lines ◽  
Mutation Frequency ◽  
Damage Tolerance ◽  
Ring Finger ◽  
Vital Role ◽  
Dna Lesions ◽  
Double Knockout ◽  
Dna Damage Tolerance

Helicase-like transcription factor (HLTF) and SNF2, histone-linker, PHD and RING finger domain-containing helicase (SHPRH), the two human homologs of yeast Rad5, are believed to have a vital role in DNA damage tolerance (DDT). Here we show that HLTF, SHPRH and HLTF/SHPRH knockout cell lines show different sensitivities towards UV-irradiation, methyl methanesulfonate (MMS), cisplatin and mitomycin C (MMC), which are drugs that induce different types of DNA lesions. In general, the HLTF/SHPRH double knockout cell line was less sensitive than the single knockouts in response to all drugs, and interestingly, especially to MMS and cisplatin. Using the SupF assay, we detected an increase in the mutation frequency in HLTF knockout cells both after UV- and MMS-induced DNA lesions, while we detected a decrease in mutation frequency over UV lesions in the HLTF/SHPRH double knockout cells. No change in the mutation frequency was detected in the HLTF/SHPRH double knockout cell line after MMS treatment, even though these cells were more resistant to MMS and grew faster than the other cell lines after treatment with DNA damaging agents. This phenotype could possibly be explained by a reduced activation of checkpoint kinase 2 (CHK2) and MCM2 (a component of the pre-replication complex) after MMS treatment in cells lacking SHPRH. Our data reveal both distinct and common roles of the human RAD5 homologs dependent on the nature of DNA lesions, and identified SHPRH as a regulator of CHK2, a central player in DNA damage response.

scholarly journals The splicing factor XAB2 interacts with ERCC1-XPF and XPG for R-loop processing

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Evi Goulielmaki ◽  
Maria Tsekrekou ◽  
Nikos Batsiotos ◽  
Mariana Ascensão-Ferreira ◽  
Eleftheria Ledaki ◽  
...  
Keyword(s):  
Dna Damage ◽  
Rna Splicing ◽  
Excision Repair ◽  
Intron Retention ◽  
Dna Lesions ◽  
Splicing Factor ◽  
Loop Formation ◽  
Rna Targets ◽  
Underlying Mechanisms

AbstractRNA splicing, transcription and the DNA damage response are intriguingly linked in mammals but the underlying mechanisms remain poorly understood. Using an in vivo biotinylation tagging approach in mice, we show that the splicing factor XAB2 interacts with the core spliceosome and that it binds to spliceosomal U4 and U6 snRNAs and pre-mRNAs in developing livers. XAB2 depletion leads to aberrant intron retention, R-loop formation and DNA damage in cells. Studies in illudin S-treated cells and Csbm/m developing livers reveal that transcription-blocking DNA lesions trigger the release of XAB2 from all RNA targets tested. Immunoprecipitation studies reveal that XAB2 interacts with ERCC1-XPF and XPG endonucleases outside nucleotide excision repair and that the trimeric protein complex binds RNA:DNA hybrids under conditions that favor the formation of R-loops. Thus, XAB2 functionally links the spliceosomal response to DNA damage with R-loop processing with important ramifications for transcription-coupled DNA repair disorders.

scholarly journals Novel conserved motifs in Rev1 C-terminus are required for mutagenic DNA damage tolerance

DNA Repair ◽  
2008 ◽  
Vol 7 (9) ◽  
pp. 1455-1470 ◽  
Author(s):  
Sanjay D'Souza ◽  
Lauren S. Waters ◽  
Graham C. Walker
Keyword(s):  
Dna Damage ◽  
Damage Tolerance ◽  
Dna Damage Tolerance ◽  
Conserved Motifs ◽  
C Terminus

scholarly journals Genomic and functional integrity of the hematopoietic system requires tolerance of oxidative DNA lesions

Blood ◽  
2017 ◽  
Vol 130 (13) ◽  
pp. 1523-1534 ◽  
Author(s):  
Ana Martín-Pardillos ◽  
Anastasia Tsaalbi-Shtylik ◽  
Si Chen ◽  
Seka Lazare ◽  
Ronald P. van Os ◽  
...  
Keyword(s):  
Dna Damage ◽  
Mitochondrial Dysfunction ◽  
Replication Stress ◽  
Precursor Cells ◽  
Dna Lesions ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
Functional Integrity ◽  
Key Points

Key Points Tolerance of oxidative DNA lesions ensures the genomic and functional integrity of hematopoietic stem and precursor cells. Endogenous DNA damage–induced replication stress is associated with mitochondrial dysfunction.

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