Interplay between DNA replication stress, chromatin dynamics and DNA-damage response for the maintenance of genome stability

2021 ◽  
Vol 787 ◽  
pp. 108346
Author(s):  
Maddalena Mognato ◽  
Susanne Burdak-Rothkamm ◽  
Kai Rothkamm
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Dna Damage Response ◽  
Genome Stability ◽  
Replication Stress ◽  
Chromatin Dynamics ◽  
Damage Response ◽  
Dna Replication Stress

scholarly journals Dissecting DNA damage response pathways by analysing protein localization and abundance changes during DNA replication stress

2012 ◽  
Vol 14 (9) ◽  
pp. 966-976 ◽  
Author(s):  
Johnny M. Tkach ◽  
Askar Yimit ◽  
Anna Y. Lee ◽  
Michael Riffle ◽  
Michael Costanzo ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Dna Damage Response ◽  
Protein Localization ◽  
Replication Stress ◽  
Damage Response ◽  
Dna Replication Stress

scholarly journals Identification of S-phase DNA damage-response targets in fission yeast reveals conservation of damage-response networks

2016 ◽  
Vol 113 (26) ◽  
pp. E3676-E3685 ◽  
Author(s):  
Nicholas A. Willis ◽  
Chunshui Zhou ◽  
Andrew E. H. Elia ◽  
Johanne M. Murray ◽  
Antony M. Carr ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Dna Replication ◽  
Fission Yeast ◽  
Dna Damage Response ◽  
Cellular Response ◽  
Genome Stability ◽  
Biological Significance ◽  
S Phase ◽  
Damage Response

The cellular response to DNA damage during S-phase regulates a complicated network of processes, including cell-cycle progression, gene expression, DNA replication kinetics, and DNA repair. In fission yeast, this S-phase DNA damage response (DDR) is coordinated by two protein kinases: Rad3, the ortholog of mammalian ATR, and Cds1, the ortholog of mammalian Chk2. Although several critical downstream targets of Rad3 and Cds1 have been identified, most of their presumed targets are unknown, including the targets responsible for regulating replication kinetics and coordinating replication and repair. To characterize targets of the S-phase DDR, we identified proteins phosphorylated in response to methyl methanesulfonate (MMS)-induced S-phase DNA damage in wild-type, rad3∆, and cds1∆ cells by proteome-wide mass spectrometry. We found a broad range of S-phase–specific DDR targets involved in gene expression, stress response, regulation of mitosis and cytokinesis, and DNA replication and repair. These targets are highly enriched for proteins required for viability in response to MMS, indicating their biological significance. Furthermore, the regulation of these proteins is similar in fission and budding yeast, across 300 My of evolution, demonstrating a deep conservation of S-phase DDR targets and suggesting that these targets may be critical for maintaining genome stability in response to S-phase DNA damage across eukaryotes.

scholarly journals FANCM suppresses DNA replication stress at ALT telomeres by disrupting TERRA R-loops

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Xiaolei Pan ◽  
Yun Chen ◽  
Beena Biju ◽  
Naveed Ahmed ◽  
Joyce Kong ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Replication Stress ◽  
Checkpoint Kinases ◽  
Alternative Lengthening ◽  
Pml Bodies ◽  
Damage Response ◽  
Dna Replication Stress ◽  
The Many ◽  
Break Induced Replication

AbstractCancer cells maintain their telomeres by either re-activating telomerase or adopting the homologous recombination (HR)-based Alternative Lengthening of Telomere (ALT) pathway. Among the many prominent features of ALT cells, C-circles (CC) formation is considered to be the most specific and quantifiable biomarker of ALT. However, the molecular mechanism behind the initiation and maintenance of CC formation in ALT cells is still largely unknown. We reported previously that depletion of the FANCM complex (FANCM-FAAP24-MHF1&2) in ALT cells induced pronounced replication stress, which primarily takes place at their telomeres. Here, we characterized the changes in ALT associated phenotypes in cells deficient of the FANCM complex. We found that depletion of FAAP24 or FANCM, but not MHF1&2, induces a dramatic increase of CC formation. Most importantly, we identified multiple DNA damage response (DDR) and DNA repair pathways that stimulate the dramatic increase of CC formation in FANCM deficient cells, including the dissolvase complex (BLM-TOP3A-RMI1/2, or BTR), DNA damage checkpoint kinases (ATR and Chk1), HR proteins (BRCA2, PALB2, and Rad51), as well as proteins involved in Break-Induced Replication (BIR) (POLD1 and POLD3). In addition, FANCD2, another Fanconi Anemia (FA) protein, is also required for CC formation, likely through promoting the recruitment of BLM to the replication stressed ALT telomeres. Finally, we demonstrated that TERRA R-loops accumulate at telomeres in FANCM deficient ALT cells and downregulation of which attenuates the ALT-associated PML bodies (APBs), replication stress and CC formation. Taken together, our data suggest that FANCM prevents replisomes from stalling/collapsing at ALT telomeres by disrupting TERRA R-loops.

scholarly journals The Roles of SPOP in DNA Damage Response and DNA Replication

2020 ◽  
Vol 21 (19) ◽  
pp. 7293
Author(s):  
Masashi Maekawa ◽  
Shigeki Higashiyama
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Dna Damage Response ◽  
Genome Stability ◽  
Substrate Binding ◽  
Critical Role ◽  
Tumor Formation ◽  
Missense Mutations ◽  
Cellular Functions ◽  
Damage Response

Speckle-type BTB/POZ protein (SPOP) is a substrate recognition receptor of the cullin-3 (CUL3)/RING type ubiquitin E3 complex. To date, approximately 30 proteins have been identified as ubiquitinated substrates of the CUL3/SPOP complex. Pathologically, missense mutations in the substrate-binding domain of SPOP have been found in prostate and endometrial cancers. Prostate and endometrial cancer-associated SPOP mutations lose and increase substrate-binding ability, respectively. Expression of these SPOP mutants, thus, causes aberrant turnovers of the substrate proteins, leading to tumor formation. Although the molecular properties of SPOP and its cancer-associated mutants have been intensively elucidated, their cellular functions remain unclear. Recently, a number of studies have uncovered the critical role of SPOP and its mutants in DNA damage response and DNA replication. In this review article, we summarize the physiological functions of SPOP as a “gatekeeper” of genome stability.

Primary cilia and the DNA damage response: linking a cellular antenna and nuclear signals

2021 ◽  
Author(s):  
Ciaran G. Morrison
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Dna Replication ◽  
Dna Damage Response ◽  
Genome Stability ◽  
Developmental Disorders ◽  
Cell Periphery ◽  
Repair Gene ◽  
Control Of Gene Expression ◽  
Damage Response

The maintenance of genome stability involves integrated biochemical activities that detect DNA damage or incomplete replication, delay the cell cycle, and direct DNA repair activities on the affected chromatin. These processes, collectively termed the DNA damage response (DDR), are crucial for cell survival and to avoid disease, particularly cancer. Recent work has highlighted links between the DDR and the primary cilium, an antenna-like, microtubule-based signalling structure that extends from a centriole docked at the cell surface. Ciliary dysfunction gives rise to a range of complex human developmental disorders termed the ciliopathies. Mutations in ciliopathy genes have been shown to impact on several functions that relate to centrosome integrity, DNA damage signalling, responses to problems in DNA replication and the control of gene expression. This review covers recent findings that link cilia and the DDR and explores the various roles played by key genes in these two contexts. It outlines how proteins encoded by ciliary genes impact checkpoint signalling, DNA replication and repair, gene expression and chromatin remodelling. It discusses how these diverse activities may integrate nuclear responses with those that affect a structure of the cell periphery. Additional directions for exploration of the interplay between these pathways are highlighted, with a focus on new ciliary gene candidates that alter genome stability.

scholarly journals More than Meets the ISG15: Emerging Roles in the DNA Damage Response and Beyond

Biomolecules ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 1557
Author(s):  
Zac Sandy ◽  
Isabelle Cristine da Costa ◽  
Christine K. Schmidt
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Dna Damage Response ◽  
Genome Stability ◽  
Post Translational Modifications ◽  
Free Dna ◽  
Damage Response ◽  
Dna Replication And Repair ◽  
Health And Disease ◽  
Interferon Stimulated Gene 15

Maintenance of genome stability is a crucial priority for any organism. To meet this priority, robust signalling networks exist to facilitate error-free DNA replication and repair. These signalling cascades are subject to various regulatory post-translational modifications that range from simple additions of chemical moieties to the conjugation of ubiquitin-like proteins (UBLs). Interferon Stimulated Gene 15 (ISG15) is one such UBL. While classically thought of as a component of antiviral immunity, ISG15 has recently emerged as a regulator of genome stability, with key roles in the DNA damage response (DDR) to modulate p53 signalling and error-free DNA replication. Additional proteomic analyses and cancer-focused studies hint at wider-reaching, uncharacterised functions for ISG15 in genome stability. We review these recent discoveries and highlight future perspectives to increase our understanding of this multifaceted UBL in health and disease.

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