scholarly journals Nucleolar Localization and Dynamic Roles of Flap Endonuclease 1 in Ribosomal DNA Replication and Damage Repair

2008 ◽  
Vol 28 (13) ◽  
pp. 4310-4319 ◽  
Author(s):  
Zhigang Guo ◽  
Limin Qian ◽  
Ren Liu ◽  
Huifang Dai ◽  
Mian Zhou ◽  
...  
Keyword(s):  
Dna Replication ◽  
Genome Stability ◽  
Phosphorylation Site ◽  
Replication Forks ◽  
Repair Capacity ◽  
Flap Endonuclease 1 ◽  
Damage Repair ◽  
Dependent Endonuclease ◽  
Cross Links ◽  
Cellular Compartmentalization

ABSTRACT Despite the wealth of information available on the biochemical functions and our recent findings of its roles in genome stability and cancer avoidance of the structure-specific flap endonuclease 1 (FEN1), its cellular compartmentalization and dynamics corresponding to its involvement in various DNA metabolic pathways are not yet elucidated. Several years ago, we demonstrated that FEN1 migrates into the nucleus in response to DNA damage and under certain cell cycle conditions. In the current paper, we found that FEN1 is superaccumulated in the nucleolus and plays a role in the resolution of stalled DNA replication forks formed at the sites of natural replication fork barriers. In response to UV irradiation and upon phosphorylation, FEN1 migrates to nuclear plasma to participate in the resolution of UV cross-links on DNA, most likely employing its concerted action of exonuclease and gap-dependent endonuclease activities. Based on yeast complementation experiments, the mutation of Ser187Asp, mimicking constant phosphorylation, excludes FEN1 from nucleolar accumulation. The replacement of Ser187 by Ala, eliminating the only phosphorylation site, retains FEN1 in nucleoli. Both of the mutations cause UV sensitivity, impair cellular UV damage repair capacity, and decline overall cellular survivorship.

scholarly journals ING2 controls the progression of DNA replication forks to maintain genome stability

EMBO Reports ◽  
2009 ◽  
Vol 10 (10) ◽  
pp. 1168-1174 ◽  
Author(s):  
Delphine Larrieu ◽  
Damien Ythier ◽  
Romuald Binet ◽  
Christian Brambilla ◽  
Elisabeth Brambilla ◽  
...  
Keyword(s):  
Dna Replication ◽  
Genome Stability ◽  
Replication Forks ◽  
Maintain Genome Stability

scholarly journals The ERCC1/XPF endonuclease is required for completion of homologous recombination at DNA replication forks stalled by inter-strand cross-links

2009 ◽  
Vol 37 (19) ◽  
pp. 6400-6413 ◽  
Author(s):  
A. Z. Al-Minawi ◽  
Y.-F. Lee ◽  
D. Hakansson ◽  
F. Johansson ◽  
C. Lundin ◽  
...  
Keyword(s):  
Dna Replication ◽  
Homologous Recombination ◽  
Replication Forks ◽  
Cross Links

scholarly journals Chromatin remodeler Fft3 plays a dual role at blocked DNA replication forks

2019 ◽  
Vol 2 (5) ◽  
pp. e201900433 ◽  
Author(s):  
Anissia Ait-Saada ◽  
Olga Khorosjutina ◽  
Jiang Chen ◽  
Karol Kramarz ◽  
Vladimir Maksimov ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Fission Yeast ◽  
Chromatin Remodeling ◽  
Replication Fork ◽  
Strand Break ◽  
Replication Forks ◽  
Damage Repair ◽  
Single Strand Annealing ◽  
Strand Annealing

Here, we investigate the function of fission yeast Fun30/Smarcad1 family of SNF2 ATPase-dependent chromatin remodeling enzymes in DNA damage repair. There are three Fun30 homologues in fission yeast, Fft1, Fft2, and Fft3. We find that only Fft3 has a function in DNA repair and it is needed for single-strand annealing of an induced double-strand break. Furthermore, we use an inducible replication fork barrier system to show that Fft3 has two distinct roles at blocked DNA replication forks. First, Fft3 is needed for the resection of nascent strands, and second, it is required to restart the blocked forks. The latter function is independent of its ATPase activity.

scholarly journals Werner Syndrome Protein and DNA Replication

2018 ◽  
Vol 19 (11) ◽  
pp. 3442 ◽  
Author(s):  
Shibani Mukherjee ◽  
Debapriya Sinha ◽  
Souparno Bhattacharya ◽  
Kalayarasan Srinivasan ◽  
Salim Abdisalaam ◽  
...  
Keyword(s):  
Dna Replication ◽  
Ataxia Telangiectasia ◽  
Replication Fork ◽  
Genome Stability ◽  
Werner Syndrome ◽  
Genotoxic Stress ◽  
Premature Aging ◽  
Replication Forks ◽  
Werner Syndrome Protein ◽  
Syndrome Protein

Werner Syndrome (WS) is an autosomal recessive disorder characterized by the premature development of aging features. Individuals with WS also have a greater predisposition to rare cancers that are mesenchymal in origin. Werner Syndrome Protein (WRN), the protein mutated in WS, is unique among RecQ family proteins in that it possesses exonuclease and 3′ to 5′ helicase activities. WRN forms dynamic sub-complexes with different factors involved in DNA replication, recombination and repair. WRN binding partners either facilitate its DNA metabolic activities or utilize it to execute their specific functions. Furthermore, WRN is phosphorylated by multiple kinases, including Ataxia telangiectasia mutated, Ataxia telangiectasia and Rad3 related, c-Abl, Cyclin-dependent kinase 1 and DNA-dependent protein kinase catalytic subunit, in response to genotoxic stress. These post-translational modifications are critical for WRN to function properly in DNA repair, replication and recombination. Accumulating evidence suggests that WRN plays a crucial role in one or more genome stability maintenance pathways, through which it suppresses cancer and premature aging. Among its many functions, WRN helps in replication fork progression, facilitates the repair of stalled replication forks and DNA double-strand breaks associated with replication forks, and blocks nuclease-mediated excessive processing of replication forks. In this review, we specifically focus on human WRN’s contribution to replication fork processing for maintaining genome stability and suppressing premature aging. Understanding WRN’s molecular role in timely and faithful DNA replication will further advance our understanding of the pathophysiology of WS.

scholarly journals EMP3 negatively modulates breast cancer cell DNA replication, DNA damage repair, and stem-like properties

2021 ◽  
Vol 12 (9) ◽  
Author(s):  
Kailing Zhou ◽  
Yu Sun ◽  
Dan Dong ◽  
Chenghai Zhao ◽  
Wei Wang
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Dna Replication ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Dna Damage Repair ◽  
Repair Capacity ◽  
Damage Repair

AbstractEnhanced DNA damage repair capacity attenuates cell killing of DNA-damaging chemotherapeutic agents. In silico analysis showed that epithelial membrane protein 3 (EMP3) is associated with favorable survival, and negatively regulates cell cycle S-phase. Consistently, loss and gain of function studies demonstrated that EMP3 inhibits breast cancer cell S-phage entry, DNA replication, DNA damage repair, and stem-like properties. Moreover, EMP3 blocks Akt-mTOR signaling activation and induces autophagy. EMP3 negatively modulates BRCA1 and RAD51 expression, indicating EMP3 suppresses homologous recombination repair of DNA double-strand breaks. Accordingly, EMP3 sensitizes breast cancer cells to the DNA-damaging drug Adriamycin. EMP3 downregulates YTHDC1, a RNA-binding protein involved in m6a modification, which at least in part mediates the effects of EMP3 on breast cancer cells. Taken together, these data indicate that EMP3 is a putative tumor suppressor in breast cancer, and EMP3 downregulation may be responsible for breast cancer chemoresistance.

scholarly journals A new role of the Mus81 nuclease for replication completion after fork restart

2019 ◽  
Author(s):  
Benjamin Pardo ◽  
María Moriel-Carretero ◽  
Thibaud Vicat ◽  
Andrés Aguilera ◽  
Philippe Pasero
Keyword(s):  
Dna Replication ◽  
Topoisomerase I ◽  
Genome Stability ◽  
Molecular Level ◽  
Dna Supercoiling ◽  
Replication Forks ◽  
Dna Topoisomerase ◽  
Replication Restart ◽  
Protein Crosslinks

ABSTRACTImpediments to DNA replication threaten genome stability. The homologous recombination (HR) pathway is involved in the restart of blocked replication forks. Here, we used a new method to study at the molecular level the restart of replication in response to DNA topoisomerase I poisoning by camptothecin (CPT). We show that HR-mediated restart at the global genomic level occurs by a BIR-like mechanism that requires Rad52, Rad51 and Pol32. The Mus81 endonuclease, previously proposed to cleave blocked forks, is not required for replication restart in S phase but appears to be essential to resolve fork-associated recombination intermediates in G2/M as a step necessary to complete replication. We confirmed our results using an independent system that allowed us to conclude that this mechanism is independent of the accumulation of DNA supercoiling and DNA-protein crosslinks normally caused by CPT. Thus, we describe here a specific function for Mus81 in the processing of HR-restarted forks required to complete DNA replication.

scholarly journals TRAIP is a PCNA-binding ubiquitin ligase that protects genome stability after replication stress

2015 ◽  
Vol 212 (1) ◽  
pp. 63-75 ◽  
Author(s):  
Saskia Hoffmann ◽  
Stine Smedegaard ◽  
Kyosuke Nakamura ◽  
Gulnahar B. Mortuza ◽  
Markus Räschle ◽  
...  
Keyword(s):  
Dna Replication ◽  
Ubiquitin Ligase ◽  
Genome Stability ◽  
Replication Stress ◽  
Nuclear Antigen ◽  
Replication Forks ◽  
Chromosomal Dna ◽  
Checkpoint Signaling ◽  
Processivity Factor ◽  
Proliferating Cell

Cellular genomes are highly vulnerable to perturbations to chromosomal DNA replication. Proliferating cell nuclear antigen (PCNA), the processivity factor for DNA replication, plays a central role as a platform for recruitment of genome surveillance and DNA repair factors to replication forks, allowing cells to mitigate the threats to genome stability posed by replication stress. We identify the E3 ubiquitin ligase TRAIP as a new factor at active and stressed replication forks that directly interacts with PCNA via a conserved PCNA-interacting peptide (PIP) box motif. We show that TRAIP promotes ATR-dependent checkpoint signaling in human cells by facilitating the generation of RPA-bound single-stranded DNA regions upon replication stress in a manner that critically requires its E3 ligase activity and is potentiated by the PIP box. Consequently, loss of TRAIP function leads to enhanced chromosomal instability and decreased cell survival after replication stress. These findings establish TRAIP as a PCNA-binding ubiquitin ligase with an important role in protecting genome integrity after obstacles to DNA replication.

scholarly journals The FANC/BRCA Pathway Releases Replication Blockades by Eliminating DNA Interstrand Cross-Links

Genes ◽  
2020 ◽  
Vol 11 (5) ◽  
pp. 585 ◽  
Author(s):  
Xavier Renaudin ◽  
Filippo Rosselli
Keyword(s):  
Dna Replication ◽  
Fanconi Anemia ◽  
Leukemic Cells ◽  
Cancer Drug ◽  
Replication Forks ◽  
Major Barrier ◽  
Cancer Drug Resistance ◽  
Interstrand Cross Links ◽  
Chromosome Fragility ◽  
Cross Links

DNA interstrand cross-links (ICLs) represent a major barrier blocking DNA replication fork progression. ICL accumulation results in growth arrest and cell death—particularly in cell populations undergoing high replicative activity, such as cancer and leukemic cells. For this reason, agents able to induce DNA ICLs are widely used as chemotherapeutic drugs. However, ICLs are also generated in cells as byproducts of normal metabolic activities. Therefore, every cell must be capable of rescuing lCL-stalled replication forks while maintaining the genetic stability of the daughter cells in order to survive, replicate DNA and segregate chromosomes at mitosis. Inactivation of the Fanconi anemia/breast cancer-associated (FANC/BRCA) pathway by inherited mutations leads to Fanconi anemia (FA), a rare developmental, cancer-predisposing and chromosome-fragility syndrome. FANC/BRCA is the key hub for a complex and wide network of proteins that—upon rescuing ICL-stalled DNA replication forks—allows cell survival. Understanding how cells cope with ICLs is mandatory to ameliorate ICL-based anticancer therapies and provide the molecular basis to prevent or bypass cancer drug resistance. Here, we review our state-of-the-art understanding of the mechanisms involved in ICL resolution during DNA synthesis, with a major focus on how the FANC/BRCA pathway ensures DNA strand opening and prevents genomic instability.

scholarly journals OsMre11 Is Required for Mitosis during Rice Growth and Development

2020 ◽  
Vol 22 (1) ◽  
pp. 169
Author(s):  
Miaomiao Shen ◽  
Yanshen Nie ◽  
Yueyue Chen ◽  
Xiufeng Zhang ◽  
Jie Zhao
Keyword(s):  
Cell Cycle ◽  
Dna Replication ◽  
Genome Stability ◽  
Mitotic Cell ◽  
Mitotic Cell Cycle ◽  
Loss Of Function ◽  
Damage Repair ◽  
Dna Replication And Repair ◽  
Dna Strand ◽  
Vegetative And Reproductive Growth

Meiotic recombination 11 (Mre11) is a relatively conserved nuclease in various species. Mre11 plays important roles in meiosis and DNA damage repair in yeast, humans and Arabidopsis, but little research has been done on mitotic DNA replication and repair in rice. Here, it was found that Mre11 was an extensively expressed gene among the various tissues and organs of rice, and loss-of-function of Mre11 resulted in severe defects of vegetative and reproductive growth, including dwarf plants, abnormally developed male and female gametes, and completely abortive seeds. The decreased number of cells in the apical meristem and the appearance of chromosomal fragments and bridges during the mitotic cell cycle in rice mre11 mutant roots revealed an essential role of OsMre11. Further research showed that DNA replication was suppressed, and a large number of DNA strand breaks occurred during the mitotic cell cycle of rice mre11 mutants. The expression of OsMre11 was up-regulated with the treatment of hydroxyurea and methyl methanesulfonate. Moreover, OsMre11 could form a complex with OsRad50 and OsNbs1, and they might function together in non-homologous end joining and homologous recombination repair pathways. These results indicated that OsMre11 plays vital roles in DNA replication and damage repair of the mitotic cell cycle, which ensure the development and fertility of rice by maintaining genome stability.

scholarly journals SDE2 Integrates into the TIMELESS-TIPIN Complex to Protect Stalled Replication Forks

2020 ◽  
Author(s):  
Julie Rageul ◽  
Jennifer J. Park ◽  
Ping Ping Zeng ◽  
Eun-A Lee ◽  
Jihyeon Yang ◽  
...  
Keyword(s):  
Dna Replication ◽  
Replication Fork ◽  
Genome Stability ◽  
Essential Role ◽  
Replication Stress ◽  
Replication Forks ◽  
Genomic Integrity ◽  
Fork Protection Complex ◽  
Stalled Replication Forks ◽  
Stalled Fork

ABSTRACTProtecting replication fork integrity during DNA replication is essential for maintaining genome stability. Here, we report that SDE2, a PCNA-associated protein, plays a key role in maintaining active replication and counteracting replication stress by regulating the replication fork protection complex (FPC). SDE2 directly interacts with the FPC component TIMELESS (TIM) and enhances TIM stability and its localization to replication forks, thereby aiding the coordination of replisome progression. Like TIM deficiency, knockdown of SDE2 leads to impaired fork progression and stalled fork recovery, along with a failure to activate CHK1 phosphorylation. Moreover, loss of SDE2 or TIM results in an excessive MRE11-dependent degradation of reversed forks. Together, our study uncovers an essential role for SDE2 in maintaining genomic integrity by stabilizing the FPC and describes a new role for TIM in protecting stalled replication forks. We propose that TIM-mediated fork protection may represent a way to cooperate with BRCA-dependent fork stabilization.

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