scholarly journals DNA2 in Chromosome Stability and Cell Survival—Is It All about Replication Forks?

2021 ◽  
Vol 22 (8) ◽  
pp. 3984
Author(s):  
Jessica J. R. Hudson ◽  
Ulrich Rass
Keyword(s):  
Replication Stress ◽  
Strand Break ◽  
Replication Forks ◽  
Phenotypic Data ◽  
Checkpoint Activation ◽  
Dna Double Strand Break ◽  
Promising Target ◽  
Anti Cancer ◽  
Okazaki Fragment Processing ◽  
Response And Recovery

The conserved nuclease-helicase DNA2 has been linked to mitochondrial myopathy, Seckel syndrome, and cancer. Across species, the protein is indispensable for cell proliferation. On the molecular level, DNA2 has been implicated in DNA double-strand break (DSB) repair, checkpoint activation, Okazaki fragment processing (OFP), and telomere homeostasis. More recently, a critical contribution of DNA2 to the replication stress response and recovery of stalled DNA replication forks (RFs) has emerged. Here, we review the available functional and phenotypic data and propose that the major cellular defects associated with DNA2 dysfunction, and the links that exist with human disease, can be rationalized through the fundamental importance of DNA2-dependent RF recovery to genome duplication. Being a crucial player at stalled RFs, DNA2 is a promising target for anti-cancer therapy aimed at eliminating cancer cells by replication-stress overload.

scholarly journals 53BP1 Mediates ATR-Chk1 Signaling and Protects Replication Forks under Conditions of Replication Stress

2018 ◽  
Vol 38 (8) ◽  
Author(s):  
Joonyoung Her ◽  
Chandni Ray ◽  
Jake Altshuler ◽  
Haiyan Zheng ◽  
Samuel F. Bunting
Keyword(s):  
Cell Death ◽  
Cellular Response ◽  
Ex Vivo ◽  
Replication Stress ◽  
Strand Break ◽  
Replication Forks ◽  
P53 Signaling ◽  
Dna Double Strand Break ◽  
Short Term Exposure ◽  
Stress Signal

ABSTRACTComplete replication of the genome is an essential prerequisite for normal cell division, but a variety of factors can block the replisome, triggering replication stress and potentially causing mutation or cell death. The cellular response to replication stress involves recruitment of proteins to stabilize the replication fork and transmit a stress signal to pause the cell cycle and allow fork restart. We find that the ubiquitously expressed DNA damage response factor 53BP1 is required for the normal response to replication stress. Using primary,ex vivoB cells, we showed that a population of 53BP1−/−cells in early S phase is hypersensitive to short-term exposure to three different agents that induce replication stress. 53BP1 localizes to a subset of replication forks following induced replication stress, and an absence of 53BP1 leads to defective ATR-Chk1-p53 signaling and caspase 3-mediated cell death. Nascent replicated DNA additionally undergoes degradation in 53BP1−/−cells. These results show that 53BP1 plays an important role in protecting replication forks during the cellular response to replication stress, in addition to the previously characterized role of 53BP1 in DNA double-strand break repair.

scholarly journals Limiting homologous recombination at stalled replication forks is essential for cell viability: DNA2 to the rescue

2020 ◽  
Vol 66 (6) ◽  
pp. 1085-1092 ◽  
Author(s):  
Rowin Appanah ◽  
David Jones ◽  
Benoît Falquet ◽  
Ulrich Rass
Keyword(s):  
Homologous Recombination ◽  
Cell Survival ◽  
Strand Break ◽  
Genome Replication ◽  
Replication Forks ◽  
Okazaki Fragment ◽  
Dna Double Strand Break ◽  
Replication Restart ◽  
Okazaki Fragment Processing ◽  
Dna End Resection

Abstract The disease-associated nuclease–helicase DNA2 has been implicated in DNA end-resection during DNA double-strand break repair, Okazaki fragment processing, and the recovery of stalled DNA replication forks (RFs). Its role in Okazaki fragment processing has been proposed to explain why DNA2 is indispensable for cell survival across organisms. Unexpectedly, we found that DNA2 has an essential role in suppressing homologous recombination (HR)-dependent replication restart at stalled RFs. In the absence of DNA2-mediated RF recovery, excessive HR-restart of stalled RFs results in toxic levels of abortive recombination intermediates that lead to DNA damage-checkpoint activation and terminal cell-cycle arrest. While HR proteins protect and restart stalled RFs to promote faithful genome replication, these findings show how HR-dependent replication restart is actively constrained by DNA2 to ensure cell survival. These new insights disambiguate the effects of DNA2 dysfunction on cell survival, and provide a framework to rationalize the association of DNA2 with cancer and the primordial dwarfism disorder Seckel syndrome based on its role in RF recovery.

scholarly journals Proteome dynamics at broken replication forks reveal a distinct ATM-directed repair response suppressing DNA double-strand break ubiquitination

2021 ◽  
Author(s):  
Kyosuke Nakamura ◽  
Georg Kustatscher ◽  
Constance Alabert ◽  
Martina Hödl ◽  
Ignasi Forne ◽  
...  
Keyword(s):  
Strand Break ◽  
Double Strand Break ◽  
Replication Forks ◽  
Dna Double Strand Break

Structural insights into DNA double-strand break signaling

2021 ◽  
Vol 478 (1) ◽  
pp. 135-156
Author(s):  
Rashmi Panigrahi ◽  
J. N. Mark Glover
Keyword(s):  
Strand Break ◽  
Double Strand Break ◽  
Signaling Proteins ◽  
Protein Signaling ◽  
Strand Breaks ◽  
Large Size ◽  
Dna Double Strand Break ◽  
Break Site ◽  
Anti Cancer ◽  
Structural Principles

Genomic integrity is most threatened by double-strand breaks, which, if left unrepaired, lead to carcinogenesis or cell death. The cell generates a network of protein–protein signaling interactions that emanate from the DNA damage which are now recognized as a rich basis for anti-cancer therapy development. Deciphering the structures of signaling proteins has been an uphill task owing to their large size and complex domain organization. Recent advances in mammalian protein expression/purification and cryo-EM-based structure determination have led to significant progress in our understanding of these large multidomain proteins. This review is an overview of the structural principles that underlie some of the key signaling proteins that function at the double-strand break site. We also discuss some plausible ideas that could be considered for future structural approaches to visualize and build a more complete understanding of protein dynamics at the break site.

scholarly journals Cockayne syndrome group B protein regulates DNA double‐strand break repair and checkpoint activation

2015 ◽  
Vol 34 (10) ◽  
pp. 1399-1416 ◽  
Author(s):  
Nicole L Batenburg ◽  
Elizabeth L Thompson ◽  
Eric A Hendrickson ◽  
Xu‐Dong Zhu
Keyword(s):  
Strand Break ◽  
Double Strand Break ◽  
Cockayne Syndrome ◽  
Double Strand Break Repair ◽  
Checkpoint Activation ◽  
Dna Double Strand Break ◽  
Break Repair ◽  
Group B

scholarly journals Akt/PKB suppresses DNA damage processing and checkpoint activation in late G2

2010 ◽  
Vol 190 (3) ◽  
pp. 297-305 ◽  
Author(s):  
Naihan Xu ◽  
Nadia Hegarat ◽  
Elizabeth J. Black ◽  
Mary T. Scott ◽  
Helfrid Hochegger ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Protein A ◽  
Strand Break ◽  
Checkpoint Activation ◽  
Interacting Protein ◽  
Dna Double Strand Break ◽  
Radiation Induced ◽  
G2 Cells ◽  
Tumor Types

Using chemical genetics to reversibly inhibit Cdk1, we find that cells arrested in late G2 are unable to delay mitotic entry after irradiation. Late G2 cells detect DNA damage lesions and form γ-H2AX foci but fail to activate Chk1. This reflects a lack of DNA double-strand break processing because late G2 cells fail to recruit RPA (replication protein A), ATR (ataxia telangiectasia and Rad3 related), Rad51, or CtIP (C-terminal interacting protein) to sites of radiation-induced damage, events essential for both checkpoint activation and initiation of DNA repair by homologous recombination. Remarkably, inhibition of Akt/PKB (protein kinase B) restores DNA damage processing and Chk1 activation after irradiation in late G2. These data demonstrate a previously unrecognized role for Akt in cell cycle regulation of DNA repair and checkpoint activation. Because Akt/PKB is frequently activated in many tumor types, these findings have important implications for the evolution and therapy of such cancers.

scholarly journals Artemis-dependent DNA double-strand break formation at stalled replication forks

2013 ◽  
Vol 104 (6) ◽  
pp. 703-710 ◽  
Author(s):  
Junya Unno ◽  
Masatoshi Takagi ◽  
Jinhua Piao ◽  
Masataka Sugimoto ◽  
Fumiko Honda ◽  
...  
Keyword(s):  
Strand Break ◽  
Double Strand Break ◽  
Replication Forks ◽  
Dna Double Strand Break ◽  
Stalled Replication Forks ◽  
Break Formation

scholarly journals DDK/Hsk1 phosphorylates and targets fission yeast histone deacetylase Hst4 for degradation to stabilize stalled DNA replication forks

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Shalini Aricthota ◽  
Devyani Haldar
Keyword(s):  
Stress Response ◽  
Fission Yeast ◽  
Cancer Therapeutics ◽  
Replication Stress ◽  
S Phase ◽  
Replication Forks ◽  
Checkpoint Activation ◽  
Fork Protection Complex ◽  
And Function ◽  
Replication Initiator

In eukaryotes, paused replication forks are prone to collapse, which leads to genomic instability, a hallmark of cancer. Dbf4 Dependent Kinase (DDK)/Hsk1Cdc7 is a conserved replication initiator kinase with conflicting roles in replication stress response. Here, we show that fission yeast DDK/Hsk1 phosphorylates sirtuin, Hst4 upon replication stress at C-terminal serine residues. Phosphorylation of Hst4 by DDK marks it for degradation via the ubiquitin ligase SCFpof3. Phosphorylation defective hst4 mutant (4SA-hst4) displays defective recovery from replication stress, faulty fork restart, slow S-phase progression and decreased viability. The highly conserved Fork Protection Complex (FPC) stabilizes stalled replication forks. We found that the recruitment of FPC components, Swi1 and Mcl1 to the chromatin is compromised in the 4SA-hst4 mutant, although whole cell levels increased. These defects are dependent upon H3K56ac and independent of intra S-phase checkpoint activation. Finally, we show conservation of H3K56ac dependent regulation of Timeless, Tipin and And-1 in human cells. We propose that degradation of Hst4 via DDK increases H3K56ac, changing the chromatin state in the vicinity of stalled forks facilitating recruitment and function of FPC. Overall, this study identified a crucial role of DDK and FPC in the regulation of replication stress response with implications in cancer therapeutics.

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