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Micronutrients in Improvement of the Standard Therapy in Cancer
Published in Kedar N. Prasad, Micronutrients in Health and Disease, 2019
Overexpression of Flap endonuclease 1 (Fen1), a DNA repair-specific nuclease, appears to be involved in the development of breast cancer. Curcumin, which exhibits antioxidant and anti-inflammation activities, decreased the growth of breast cancer cells (MCF-7) in the presence of activated Nrf2. This effect of curcumin is mediated by reduced level of Fen1.74 Thus, curcumin can inhibit the growth of cancer cells in the presence of activated Nrf2 by enhancing the levels of proteins in apoptotic pathways.
Irradiation-induced damage and the DNA damage response
Published in Michael C. Joiner, Albert J. van der Kogel, Basic Clinical Radiobiology, 2018
Conchita Vens, Marianne Koritzinsky, Bradly G. Wouters
As outlined previously, one of the initial lesion sensing events is the activation of PARP and the formation of PAR on chromatin at the lesion sites. SSBs and abasic sites cause a quick PAR response that facilitates repair protein recruitment. PAR polymers are then removed by poly (ADP-ribose)-glycohydrolase (PARG). An outline of the BER and SSBR events that follow is shown in Figure 2.7. Briefly, in BER, most of the damaged bases in the DNA will be detected and removed by specialized glycosylase proteins which remove the damaged base, resulting in an abasic site. This will be recognized by an AP endonuclease (APE), which will cut the DNA backbone leaving a nick, or SSB. Subsequent repair follows one of two pathways called short patch or long patch. In short patch, the damaged base is replaced by DNA polymerase β (POLβ) in the presence of XRCC1, followed by ligation of the DNA ends by ligase 3 (LIG3). In long patch, up to 10 nucleotides surrounding the damaged site are replaced by DNA polymerase δ or ε in the presence of PCNA, while Flap endonuclease 1 (FEN1) removes the overhanging nucleotides, followed by ligation by ligase 1 (LIG1).
The Premature Aging Characteristics of RecQ Helicases
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Christ Ordookhanian, Taylor N. Dennis, J. Jefferson P. Perry
The physical and functional interactions of WRN with proteins in the DNA repair pathways, such as FEN-1, Ku70/80, RAD52, and PARP-1, strongly indicate key repair roles for WRN that may impact the clinical phenotype of WS. Links to the base excision repair (BER) pathway include physical and functional interactions with multiple BER components that include: replication protein A (RPA) [84], PCNA [85] polδ [86,87], flap endonuclease 1 (FEN-1) [83], polβ [88], and poly(ADP-ribose)polymerase 1 (PARP-1) [80]. A potential link to the nucleotide excision repair (NER) pathway is indicated by the interaction of WRN and XPG [89], while links to DNA DSB repair pathways are perhaps the most numerous. An interaction of WRN with the NHEJ-essential protein kinase DNA–PK that also has capping functions at mammalian telomeres, provided a first link to NHEJ pathway [52,90,91]. WRN is only one of the four known in vivo substrates of DNA–PK, and full-length WRN activity is regulated by both the Ku70/80 subunit and holo–DNA–PK [52,91] and WRN exonuclease activity is stimulated in vitro the DNA–PK subunit Ku70/80 [77,78,91–93]. WRN has been observed in an endogenous complex with the Ku70/80 subunit and poly(ADP-ribose) polymerase-1 (PARP-1) [94] that binds sites of SSBs and DSBs, and is also implicated in the control of genomic integrity and mammalian life span [95]. XRCC4/Ligase IV that functions in NHEJ also stimulates the exonuclease, but not the helicase activity of WRN [78,92]. Interestingly, NHEJ-mediated repair in WS cells displays extensive deletions, which suggests that another, less regulated exonuclease may substitute for WRN in these cells [96].
Targeting the DNA damage response in pediatric malignancies
Published in Expert Review of Anticancer Therapy, 2022
Jenna M Gedminas, Theodore W Laetsch
As opposed to the small base lesions corrected using BER, nucleotide excision repair (NER) removes the bulky DNA lesions caused by UV light, environmental mutagens, and cancer chemotherapy adducts [8]. Once the damage is recognized, transcription factor II H (THFIIH) and XPG are recruited to the site to act as helicases and unwind the DNA. XPG and XPF-ERCC1 then act as endonucleases to cut the DNA on either side of the damage, removing a single strand of 25–30 nucleotides. Proliferating cell nuclear antigen is loaded onto the DNA strand by replication factor C allowing DNA polymerases to copy the undamaged strand. Finally, DNA ligase I and flap endonuclease 1 seal the nicks in the repaired DNA [8]. Poly (ADP-ribose) polymerases (PARPs) are enzymes which play a role in BER and NER, as well as single stranded break repair [9]. PARP binds to sites of DNA strand breaks to facilitate access of the respective repair enzymes to the site [9]. PARP inhibition has shown synthetic lethality with BRCA mutations in the clinical and preclinical setting [9].
Frontiers of metal-coordinating drug design
Published in Expert Opinion on Drug Discovery, 2021
Giulia Palermo, Angelo Spinello, Aakash Saha, Alessandra Magistrato
Finally, magnesium-dependent proteins and ribozymes are widespread and promote the metabolism of nucleic acids in genome regulatory processes [17,18]. Among these, Mg2+-dependent pharmacological targets are (i) the flap endonuclease 1 (FEN1), an enzyme that removes the DNA and RNA flaps formed during replication and repair and is targeted by anticancer drugs [19,20]; (ii) HIV integrase, which inserts the viral genome into the host cell and is targeted by antiviral compounds [21]; (iii) the GTPase enzymes, which are critically linked with cellular differentiation, proliferation, division, and movement by regulating signal transduction. Their activity in many infiltrative (brain, ovarian, and melanoma) cancers can be inhibited by small-molecules binding to their Mg2+ ion cofactor [22].
Proteome of thymus and spleen reveals that 10-hydroxydec-2-enoic acid could enhance immunity in mice
Published in Expert Opinion on Therapeutic Targets, 2020
Pei Fan, Bin Han, Han Hu, Qiaohong Wei, Xufeng Zhang, Lifeng Meng, Jing Nie, Xiaofeng Tang, Xinyue Tian, Lu Zhang, Liping Wang, Jianke Li
The PPI network analysis, combined with GO enrichment, enables us to screen key proteins in immunological modulation of 10-HDA. For instance, MCM2, a component of the MCM2-7 complex, had highly increased (fold change 5.7) in weight-regained thymus after 10-HDA administration because of its essential role in DNA replication initiation and elongation [70]. MCM2 is highly connected (degrees 58) in the PPI network, and engages in GO terms of DNA replication, DNA unwinding involved in DNA replication, ATP-dependent chromatin remodeling, nucleosome positioning, and response to interleukin-4. Many other 10-HDA regulated proteins, such as MCM3-7, flap endonuclease 1 (FEN1), proliferating cell nuclear antigen (PCNA), replication protein A1 & A3 (RPA1 & 3), implicated in GO terms of DNA replication, are directly connected to MCM2, to function cooperatively for increasing DNA activity. PRPF19, participating in GO terms of splicesome, spliceosomal complex assembly, and positive regulation of mRNA splicing, via spliceosome in our data, is responsible for pre-mRNA splicing and functions as a sensor in DNA damage response [71]. It also connects with MCM2 in the network through different ways, suggesting these proteins are highly connected to reinforce the DNA and RNA behaviors in the thymus underlying 10-HDA regulation.