How do cells sense DNA lesions?

2020 ◽  
Vol 48 (2) ◽  
pp. 677-691 ◽  
Author(s):  
Chiara Vittoria Colombo ◽  
Marco Gnugnoli ◽  
Elisa Gobbini ◽  
Maria Pia Longhese
Keyword(s):  
Dna Damage ◽  
Protein Complexes ◽  
Dna Lesions ◽  
Exogenous Dna ◽  
Cellular Targets ◽  
Cellular Processes ◽  
Dna Lesion ◽  
Dna Damaging Agents ◽  
Wide Range ◽  
Damage Response

DNA is exposed to both endogenous and exogenous DNA damaging agents that chemically modify it. To counteract the deleterious effects exerted by DNA lesions, eukaryotic cells have evolved a network of cellular pathways, termed DNA damage response (DDR). The DDR comprises both mechanisms devoted to repair DNA lesions and signal transduction pathways that sense DNA damage and transduce this information to specific cellular targets. These targets, in turn, impact a wide range of cellular processes including DNA replication, DNA repair and cell cycle transitions. The importance of the DDR is highlighted by the fact that DDR inactivation is commonly found in cancer and causes many different human diseases. The protein kinases ATM and ATR, as well as their budding yeast orthologs Tel1 and Mec1, act as master regulators of the DDR. The initiating events in the DDR entail both DNA lesion recognition and assembly of protein complexes at the damaged DNA sites. Here, we review what is known about the early steps of the DDR.

scholarly journals SPINDOC binds PARP1 to facilitate PARylation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Fen Yang ◽  
Jianji Chen ◽  
Bin Liu ◽  
Guozhen Gao ◽  
Manu Sebastian ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Knockout Mice ◽  
Protein Complexes ◽  
Dna Lesions ◽  
The Other ◽  
Effector Protein ◽  
Interacting Proteins ◽  
Damage Response

AbstractSPINDOC is tightly associated with the histone H3K4me3 effector protein SPIN1. To gain a better understanding of the biological roles of SPINDOC, we identified its interacting proteins. Unexpectedly, SPINDOC forms two mutually exclusive protein complexes, one with SPIN1 and the other with PARP1. Consistent with its ability to directly interact with PARP1, SPINDOC expression is induced by DNA damage, likely by KLF4, and recruited to DNA lesions with dynamics that follows PARP1. In SPINDOC knockout cells, the levels of PARylation are reduced, in both the absence and presence of DNA damage. The SPINDOC/PARP1 interaction promotes the clearance of PARP1 from damaged DNA, and also impacts the expression of known transcriptional targets of PARP1. To address the in vivo roles of SPINDOC in PARP1 regulation, we generate SPINDOC knockout mice, which are viable, but slightly smaller than their wildtype counterparts. The KO mice display reduced levels of PARylation and, like PARP1 KO mice, are hypersensitive to IR-induced DNA damage. The findings identify a SPIN1-independent role for SPINDOC in the regulation of PARP1-mediated PARylation and the DNA damage response.

scholarly journals Unpicking the Roles of DNA Damage Protein Kinases in Trypanosomatids

2021 ◽  
Vol 9 ◽  
Author(s):  
Gabriel L. A. Silva ◽  
Luiz R. O. Tosi ◽  
Richard McCulloch ◽  
Jennifer Ann Black
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Protein Kinases ◽  
Genetic Manipulation ◽  
Excision Repair ◽  
Dna Lesions ◽  
Wide Range ◽  
Damage Response ◽  
Repair Pathways ◽  
Signal Relays

To preserve genome integrity when faced with DNA lesions, cells activate and coordinate a multitude of DNA repair pathways to ensure timely error correction or tolerance, collectively called the DNA damage response (DDR). These interconnecting damage response pathways are molecular signal relays, with protein kinases (PKs) at the pinnacle. Focused efforts in model eukaryotes have revealed intricate aspects of DNA repair PK function, including how they direct DDR pathways and how repair reactions connect to wider cellular processes, including DNA replication and transcription. The Kinetoplastidae, including many parasites like Trypanosoma spp. and Leishmania spp. (causative agents of debilitating, neglected tropical infections), exhibit peculiarities in several core biological processes, including the predominance of multigenic transcription and the streamlining or repurposing of DNA repair pathways, such as the loss of non-homologous end joining and novel operation of nucleotide excision repair (NER). Very recent studies have implicated ATR and ATM kinases in the DDR of kinetoplastid parasites, whereas DNA-dependent protein kinase (DNA-PKcs) displays uncertain conservation, questioning what functions it fulfills. The wide range of genetic manipulation approaches in these organisms presents an opportunity to investigate DNA repair kinase roles in kinetoplastids and to ask if further kinases are involved. Furthermore, the availability of kinase inhibitory compounds, targeting numerous eukaryotic PKs, could allow us to test the suitability of DNA repair PKs as novel chemotherapeutic targets. Here, we will review recent advances in the study of trypanosomatid DNA repair kinases.

scholarly journals The F-Box-Like Protein FBL17 Is a Regulator of DNA-Damage Response and Colocalizes with RETINOBLASTOMA RELATED1 at DNA Lesion Sites

2020 ◽  
Vol 183 (3) ◽  
pp. 1295-1305 ◽  
Author(s):  
Naomie Gentric ◽  
Kinda Masoud ◽  
Robin P. Journot ◽  
Valérie Cognat ◽  
Marie-Edith Chabouté ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Dna Lesion ◽  
Damage Response

scholarly journals MORC2 regulates DNA damage response through a PARP1-dependent pathway

2019 ◽  
Vol 47 (16) ◽  
pp. 8502-8520 ◽  
Author(s):  
Lin Zhang ◽  
Da-Qiang Li
Keyword(s):  
Dna Damage ◽  
Zinc Finger ◽  
Chromatin Remodeling ◽  
Dna Damage Response ◽  
Mammalian Cells ◽  
Cellular Response ◽  
Genotoxic Stress ◽  
Underlying Mechanism ◽  
Dna Lesions ◽  
Damage Response

Abstract Microrchidia family CW-type zinc finger 2 (MORC2) is a newly identified chromatin remodeling enzyme with an emerging role in DNA damage response (DDR), but the underlying mechanism remains largely unknown. Here, we show that poly(ADP-ribose) polymerase 1 (PARP1), a key chromatin-associated enzyme responsible for the synthesis of poly(ADP-ribose) (PAR) polymers in mammalian cells, interacts with and PARylates MORC2 at two residues within its conserved CW-type zinc finger domain. Following DNA damage, PARP1 recruits MORC2 to DNA damage sites and catalyzes MORC2 PARylation, which stimulates its ATPase and chromatin remodeling activities. Mutation of PARylation residues in MORC2 results in reduced cell survival after DNA damage. MORC2, in turn, stabilizes PARP1 through enhancing acetyltransferase NAT10-mediated acetylation of PARP1 at lysine 949, which blocks its ubiquitination at the same residue and subsequent degradation by E3 ubiquitin ligase CHFR. Consequently, depletion of MORC2 or expression of an acetylation-defective PARP1 mutant impairs DNA damage-induced PAR production and PAR-dependent recruitment of DNA repair proteins to DNA lesions, leading to enhanced sensitivity to genotoxic stress. Collectively, these findings uncover a previously unrecognized mechanistic link between MORC2 and PARP1 in the regulation of cellular response to DNA damage.

scholarly journals Recent advances in the nucleolar responses to DNA double-strand breaks

2020 ◽  
Vol 48 (17) ◽  
pp. 9449-9461
Author(s):  
Lea Milling Korsholm ◽  
Zita Gál ◽  
Blanca Nieto ◽  
Oliver Quevedo ◽  
Stavroula Boukoura ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Dna Damage Response ◽  
Ribosomal Dna ◽  
Repetitive Sequences ◽  
Dna Lesions ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Damage Response

Abstract DNA damage poses a serious threat to human health and cells therefore continuously monitor and repair DNA lesions across the genome. Ribosomal DNA is a genomic domain that represents a particular challenge due to repetitive sequences, high transcriptional activity and its localization in the nucleolus, where the accessibility of DNA repair factors is limited. Recent discoveries have significantly extended our understanding of how cells respond to DNA double-strand breaks (DSBs) in the nucleolus, and new kinases and multiple down-stream targets have been identified. Restructuring of the nucleolus can occur as a consequence of DSBs and new data point to an active regulation of this process, challenging previous views. Furthermore, new insights into coordination of cell cycle phases and ribosomal DNA repair argue against existing concepts. In addition, the importance of nucleolar-DNA damage response (n-DDR) mechanisms for maintenance of genome stability and the potential of such factors as anti-cancer targets is becoming apparent. This review will provide a detailed discussion of recent findings and their implications for our understanding of the n-DDR. The n-DDR shares features with the DNA damage response (DDR) elsewhere in the genome but is also emerging as an independent response unique to ribosomal DNA and the nucleolus.

scholarly journals Guanine Quadruplex DNA Regulates Gamma Radiation Response of Genome Functions in the Radioresistant Bacterium Deinococcus radiodurans

2019 ◽  
Vol 201 (17) ◽  
Author(s):  
Shruti Mishra ◽  
Reema Chaudhary ◽  
Sudhir Singh ◽  
Swathi Kota ◽  
Hari S. Misra
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Deinococcus Radiodurans ◽  
Dna Structure ◽  
Protein Translation ◽  
Content Type ◽  
Cellular Processes ◽  
G4 Dna ◽  
Guanine Quadruplex ◽  
Damage Response

ABSTRACT Guanine quadruplex (G4) DNA/RNA are secondary structures that regulate the various cellular processes in both eukaryotes and bacteria. Deinococcus radiodurans, a Gram-positive bacterium known for its extraordinary radioresistance, shows a genomewide occurrence of putative G4 DNA-forming motifs in its GC-rich genome. N-Methyl mesoporphyrin (NMM), a G4 DNA structure-stabilizing drug, did not affect bacterial growth under normal conditions but inhibited the postirradiation recovery of gamma-irradiated cells. Transcriptome sequencing analysis of cells treated with both radiation and NMM showed repression of gamma radiation-responsive gene expression, which was observed in the absence of NMM. Notably, this effect of NMM on the expression of housekeeping genes involved in other cellular processes was not observed. Stabilization of G4 DNA structures mapped at the upstream of recA and in the encoding region of DR_2199 had negatively affected promoter activity in vivo, DNA synthesis in vitro and protein translation in Escherichia coli host. These results suggested that G4 DNA plays an important role in DNA damage response and in the regulation of expression of the DNA repair proteins required for radioresistance in D. radiodurans. IMPORTANCE Deinococcus radiodurans can recover from extensive DNA damage caused by many genotoxic agents. It lacks LexA/RecA-mediated canonical SOS response. Therefore, the molecular mechanisms underlying the regulation of DNA damage response would be worth investigating in this bacterium. D. radiodurans genome is GC-rich and contains numerous islands of putative guanine quadruplex (G4) DNA structure-forming motifs. Here, we showed that in vivo stabilization of G4 DNA structures can impair DNA damage response processes in D. radiodurans. Essential cellular processes such as transcription, DNA synthesis, and protein translation, which are also an integral part of the double-strand DNA break repair pathway, are affected by the arrest of G4 DNA structure dynamics. Thus, the role of DNA secondary structures in DNA damage response and radioresistance is demonstrated.

scholarly journals The Dark Side of UV-Induced DNA Lesion Repair

Genes ◽  
2020 ◽  
Vol 11 (12) ◽  
pp. 1450
Author(s):  
Wojciech Strzałka ◽  
Piotr Zgłobicki ◽  
Ewa Kowalska ◽  
Aneta Bażant ◽  
Dariusz Dziga ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Uv Light ◽  
Genetic Material ◽  
Dna Lesions ◽  
Dark Side ◽  
Repair System ◽  
Strand Breaks ◽  
Dna Lesion ◽  
Pyrimidine Dimers

In their life cycle, plants are exposed to various unfavorable environmental factors including ultraviolet (UV) radiation emitted by the Sun. UV-A and UV-B, which are partially absorbed by the ozone layer, reach the surface of the Earth causing harmful effects among the others on plant genetic material. The energy of UV light is sufficient to induce mutations in DNA. Some examples of DNA damage induced by UV are pyrimidine dimers, oxidized nucleotides as well as single and double-strand breaks. When exposed to light, plants can repair major UV-induced DNA lesions, i.e., pyrimidine dimers using photoreactivation. However, this highly efficient light-dependent DNA repair system is ineffective in dim light or at night. Moreover, it is helpless when it comes to the repair of DNA lesions other than pyrimidine dimers. In this review, we have focused on how plants cope with deleterious DNA damage that cannot be repaired by photoreactivation. The current understanding of light-independent mechanisms, classified as dark DNA repair, indispensable for the maintenance of plant genetic material integrity has been presented.

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