• Molecules and Cells
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• 제19권2호
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• pp.167-179
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• 2005

The cells of metazoans respond to DNA damage by either arresting their cell cycle in order to repair the DNA, or by undergoing apoptosis. This response is highly conserved across species, and many of the genes involved in this DNA damage response have been shown to be inactivated in human cancers. This suggests the importance of DNA damage response with regard to the prevention of cancer. The DNA damage checkpoint responses vary greatly depending on the developmental context, cell type, gene expression profile, and the degree and nature of the DNA lesions. More valuable information can be obtained from studies utilizing whole organisms in which the molecular basis of development has been well established, such as Drosophila. Since the discovery of the Drosophila p53 orthologue, various aspects of DNA damage responses have been studied in Drosophila. In this review, I will summarize the current knowledge on the DNA damage checkpoint response in Drosophila. With the ease of genetic, cellular, and cytological approaches, Drosophila will become an increasingly valuable model organism for the study of mechanisms inherent to cancer formation associated with defects in the DNA damage pathway.

• Molecules and Cells
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• 제25권4호
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• pp.457-461
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• 2008

DNA damage checkpoint is an important self-defense mechanism for the maintenance of genome stability. Defects in DNA damage signaling and repair lead to various disorders and increase tumor incidence in humans. In the past 10 years, we have identified many components involved in the DNA damage-signaling pathway, including the product of breast cancer susceptibility gene 1 (BRCA1). Mutations in BRCA1 are associated with increased risk of breast and ovarian cancers, highlighting the importance of this DNA damage-signaling pathway in tumor suppression. While it becomes clear that BRCA1 plays a crucial role in the DNA damage responsive pathway, exactly how BRCA1 receives DNA damage signals and exerts its checkpoint function has not been fully addressed. A series of recent studies reported the discovery of many novel components involved in DNA damage-signaling pathway. These newly identified checkpoint proteins, including RNF8, RAP80 and CCDC98, work in concern in recruiting BRCA1 to DNA damage sites and thus regulate BRCA1 function in G2/M checkpoint control. This review will summarize these recent findings and provide an updated view of the regulation of BRCA1 in response to DNA damage.

• BMB Reports
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• 제47권5호
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• pp.249-255
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• 2014

Polo-like kinase-1 (Plk1) belongs to a family of serine-threonine kinases and plays a critical role in mitotic progression. Plk1 involves in the initiation of mitosis, centrosome maturation, bipolar spindle formation, and cytokinesis, well-reported as traditional functions of Plk1. In this review, we discuss the role of Plk1 during DNA damage response beyond the functions in mitotsis. When DNA is damaged in cells under various stress conditions, the checkpoint mechanism is activated to allow cells to have enough time for repair. When damage is repaired, cells progress continuously their division, which is called checkpoint recovery. If damage is too severe to repair, cells undergo apoptotic pathway. If damage is not completely repaired, cells undergo a process called checkpoint adaptation, and resume cell division cycle with damaged DNA. Plk1 targets and regulates many key factors in the process of damage response, and we deal with these subjects in this review.

• Biomolecules & Therapeutics
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• 제31권3호
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• pp.340-349
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• 2023

Mad2B (Mad2L2), the human homolog of the yeast Rev7 protein, is a regulatory subunit of DNA polymerase ζ that shares sequence similarity with the mitotic checkpoint protein Mad2A. Previous studies on Mad2B have concluded that it is a mitotic checkpoint protein that functions by inhibiting the anaphase-promoting complex/cyclosome (APC/C). Here, we demonstrate that Mad2B is activated in response to cisplatin-induced DNA damage. Mad2B co-localizes at nuclear foci with DNA damage markers, such as proliferating cell nuclear antigen and gamma histone H2AX (γ-H2AX), following cisplatin-induced DNA damage. However, unlike Mad2A, the binding of Mad2B to Cdc20 does not inhibit the activity of APC/C in vitro. In contrast to Mad2A, Mad2B does not localize to kinetochores or binds to Cdc20 in spindle assembly checkpoint-activated cells. Loss of the Mad2B protein leads to damaged nuclei following cisplatin-induced DNA damage. Mad2B/Rev7 depletion causes the accumulation of damaged nuclei, thereby accelerating apoptosis in human cancer cells in response to cisplatin-induced DNA damage. Therefore, our results suggest that Mad2B may be a critical modulator of DNA damage response.

• 미생물학회지
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• 제38권2호
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• pp.96-102
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• 2002

S기 checkpoint기작은 DNA복제 저해나 DNA상해 등에 반응하여, S기 세포주기 정지를 일으키거나 상해 회복에 관련된 유전자들의 전사가 유도됨으로서 진핵세포에서의 유전적인 안정성을 유지한다. 이러한 반응에 대한것ba11 변이주의 결손을 확인하기 위해서, nPB11 (DNA polymerase B possible subunit)유전자의 과다발현 효과에 대해 조사하고, HU (Hydroxyurea)와 MMS (Methyl methanesulfonate)에 대한 감수성 및 DNA상해 물질에 의한 RNR3 (Ribonulectide reductase) mRNA의 전사 유도를 조사하였다. RNR3 mRNA의 전사는 DNA합성 저해에 의해 발생한 스트레스나 화학물질에 의한 직접적 인 DNA상해 등에 의해 유도되어진다. 그 결과, dpb11-1변이주는 DNA상해 물질에 감수성을 나타내었고, RNR3 mRNA전사유도 또한 야생형 균주에 비해 약 40% 정도 감소를 나타내었다. 더욱이 dpb2-1 균주에서도 이와 동일한 결과를 얻었다. 그러므로 DPB2와 DPB11 유전자는 복제에 대한 sensor로서, 복제 정지 요인에 대한 세포주기 반응과 전사 조절에 모두 작용하는 것으로 사료된다.

• BMB Reports
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• 제56권3호
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• pp.166-171
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• 2023

Monocytes are peripheral leukocytes that function in innate immunity. Excessive triglyceride (TG) accumulation causes monocyte death and thus can compromise innate immunity. However, the mechanisms by which TG mediates monocyte death remain unclear to date. Thus, this study aimed to elucidate the mechanisms by which TG induces monocyte death. Results showed that TG induced monocyte death by activating caspase-3/7 and promoting poly (ADP-ribose) polymerase (PARP) cleavage. In addition, TG induced DNA damage and activated the ataxia telangiectasia mutated (ATM)/checkpoint kinase 2 and ATM-and Rad3-related (ATR)/checkpoint kinase 1 pathways, leading to the cell death. Furthermore, TG-induced DNA damage and monocyte death were mediated by caspase-2 and -8, and caspase-8 acted as an upstream molecule of caspase-2. Taken together, these results suggest that TG-induced monocyte death is mediated via the caspase-8/caspase-2/DNA damage/executioner caspase/PARP pathways.

• Journal of Microbiology and Biotechnology
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• 제13권4호
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• pp.624-627
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• 2003

Benzo[a]pyrene (B[a]P) is an environmental pollutant that has been implicated in carcinogenesis. Saccharomyces cerevisiae was treated with B[a]P, and the responses of its cytochrome P450 (CYP) enzyme and DNA-damage checkpoint genes were examined through gene expression profiles using a reverse transcription polymerase chain reaction (RT-PCR). The DNA-damage checkpoint genes tested were the chk1 and pds1 genes, involved in a metaphase arrest, the swi6 gene targeted by G1 arrest, the pol2 gene related to S phase arrest, and the cln2 gene encoding a cyclin protein, all of which are based on rad9 and rad24. Among these genes, no noticeable effect was found when the cells were exposed to various concentrations of B[a]P. However, the transcriptional activity of CYP51 was significantly different when the cells were exposed to B[a]P. Accordingly, the present results indicate that cytochrome P450 plays a more significant role than DNA-damage checkpoint genes in the response of S. cerevisiae to B[a]P.

• 생명과학회지
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• 제21권8호
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• pp.1067-1075
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• 2011

CCDC98 단백질은 BRCA1-A 복합체를 DNA 손상 부위로 이동시킴으로써 DNA손상에 의하여 유도되는 G2/M cell cycle checkpoint에 중요한 역할을 한다고 알려져 있다. 하지만 많은 연구에도 불구하고 CCDC98 단백질의 기능에 대해서 알려진 바가 거의 없다. 본 연구는 CCDC98 단백질의 기능을 밝히고자 tandem affinity purification 방법을 수행하였다. 그 결과 Wilms tumor 1-associating protein (WTAP)을 CCDC98의 결합 단백질로 분리 동정하였다. 이들 단백질의 결합을 in vivo and in vitro binding assays를 통하여 확인하였다. 또한, CCDC98 단백질이 cyclin B1의 발현을 억제함을 확인하였는데, 이는 WTAP 단백질의 발현을 조절함으로써 이루어진다는 것을 확인하였다. 이는 CCDC98 단백질이 새로운 세포주기 조절자라는 것을 증명하는 결과이다.

• The Korean Journal of Physiology and Pharmacology
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• 제27권5호
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• pp.427-436
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• 2023

Mitotic arrest deficient 2 like 2 (Mad2L2, also known as Mad2B), the human homologue of the yeast Rev7 protein, is a regulatory subunit of DNA polymerase ζ that shares high sequence homology with Mad2, the mitotic checkpoint protein. Previously, we demonstrated the involvement of Mad2B in the cisplatin-induced DNA damage response. In this study, we extend our findings to show that Mad2B is recruited to sites of DNA damage in human cancer cells in response to cisplatin treatment. We found that in undamaged cells, Mad2B exists in a complex with Polζ-Rev1 and the APC/C subunit Cdc27. Following cisplatin-induced DNA damage, we observed an increase in the recruitment of Mad2B and Cdc20 (the activators of the APC/C), to the complex. The involvement of Mad2B-Cdc20-APC/C during DNA damage has not been reported before and suggests that the APC/C is activated following cisplatin-induced DNA damage. Using an in vitro ubiquitination assay, our data confirmed Mad2B-dependent activation of APC/C in cisplatin-treated cells. Mad2B may act as an accelerator for APC/C activation during DNA damage response. Our data strongly suggest a role for Mad2B-APC/C-Cdc20 in the ubiquitination of proteins involved in the DNA damage response.

• 한국자원식물학회:학술대회논문집
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• 한국자원식물학회 2021년도 춘계학술대회
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• pp.52-52
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• 2021

Persicaria amphibia as an England native plant, is a rhizomatous perennial, one of the rather amphibious plants. Its aquatic form contains water-soluble sugars, starch, and protein. P. amphibia have up to 18% tannins in stems and rhizomes. Previous studies have confirmed the anti-inflammatory activity of live bacteria roots, but no studies on bioactivity are known. DNA damage responses (DDRs) pathways are considered a crucial factor affecting the alleviation of cellular damage. The ataxia-telangiectasia mutated and Rad3 related (ATM) and checkpoint kinase 2 (Chk2) pathways are the main pathways of DNA damage response. Also, p53 is a key integrator of cellular response to oxidative DNA damage, contributing repair, or leading transcription including apoptosis. In the present study, we conducted an investigation into the inhibitory effects of P. amphibia on oxidative DNA damage for confirming potential to complementary medicine and therapies. In conclusion, P. amphibia can provide protective effects against double-stranded DNA break (DSB) caused by oxidative DNA damage.