The CDK-PLK1 axis targets the DNA damage checkpoint sensor protein RAD9 to promote cell proliferation and tolerance to genotoxic stress

Wakida, Takeshi; Ikura, Masae; Kuriya, Kenji; Ito, Shinji; Shiroiwa, Yoshiharu; Habu, Toshiyuki; Kawamoto, Takuo; Okumura, Katsuhiko; Ikura, Tsuyoshi; Furuya, Kanji

doi:10.7554/elife.29953

Cited by 20 publications

(17 citation statements)

References 78 publications

(102 reference statements)

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“…The study of the mechanisms that regulate DNA repair and other DNA damage responses through the cell cycle is evolving rapidly. There is an immense amount of detail in the literature concerning the regulation of repair and checkpoint signalling [53] by cell cycle dependent phosphorylation and ubiquitylation. In the next few years we will likely have a clearer understanding of how DNA repair pathway choice for DSBs, the most toxic of DNA lesions, is integrated with, and fine-tuned by, the cell cycle.…”

Section: Resultsmentioning

confidence: 99%

Integrating DNA damage repair with the cell cycle

Murray¹,

Carr²

2018

Current Opinion in Cell Biology

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DNA is labile and constantly subject to damage. In addition to external mutagens, DNA is continuously damaged by the aqueous environment, cellular metabolites and is prone to strand breakage during replication. Cell duplication is orchestrated by the cell division cycle and specific DNA structures are processed differently depending on where in the cell cycle they are detected. This is often because a specific structure is physiological in one context, for example during DNA replication, while indicating a potentially pathological event in another, such as interphase or mitosis. Thus, contextualising the biochemical entity with respect to cell cycle progression provides information necessary to appropriately regulate DNA processing activities. We review the links between DNA repair and cell cycle context, drawing together recent advances.

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Section: Resultsmentioning

confidence: 99%

Integrating DNA damage repair with the cell cycle

Murray¹,

Carr²

2018

Current Opinion in Cell Biology

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“…Through differential regulation at numerous subcellular locales, PLK1 displays a variety of functions as a major regulator of mitotic entry. For instance, PLK1 localizes to the nucleus during G2‐phase where it has been implicated as a DNA damage checkpoint regulator (Hyun, Hwang, Hwan, & Jang, ; Smits et al, ; Van Vugt, Brá, & Medema, ; Wakida et al, ). During this process, PLK1 is required to recruit initial components of the DNA Damage Response (DDR), including ATM/ATR (Hyun, Hwang, et al, ).…”

Section: Function Of Plk1mentioning

confidence: 99%

Regulating a key mitotic regulator, polo‐like kinase 1 (PLK1)

Colicino

Hehnly

2018

Cytoskeleton

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During cell division, duplicated genetic material is separated into two distinct daughter cells. This process is essential for initial tissue formation during development and to maintain tissue integrity throughout an organism's lifetime. To ensure the efficacy and efficiency of this process, the cell employs a variety of regulatory and signaling proteins that function as mitotic regulators and checkpoint proteins. One vital mitotic regulator is polo‐like kinase 1 (PLK1), a highly conserved member of the polo‐like kinase family. Unique from its paralogues, it functions specifically during mitosis as a regulator of cell division. PLK1 is spatially and temporally enriched at three distinct subcellular locales; the mitotic centrosomes, kinetochores, and the cytokinetic midbody. These localization patterns allow PLK1 to phosphorylate specific downstream targets to regulate mitosis. In this review, we will explore how polo‐like kinases were originally discovered and diverged into the five paralogues (PLK1‐5) in mammals. We will then focus specifically on the most conserved, PLK1, where we will discuss what is known about how its activity is modulated, its role during the cell cycle, and new, innovative tools that have been developed to examine its function and interactions in cells.

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“…PLK1 phosphorylates the Rad9 component of the Rad9A-Hus1-Rad1 (9-1-1) protein complex that localizes to sites of DNA damage and promotes checkpoint-mediated arrest through ATR and double strand DNA break (DSB) repair mechanisms. The phosphorylation of Rad9 by PLK1 suppresses this checkpoint activation [ 124 ]. DNA damage during mitosis has also been found to inhibit PLK1, although this mechanism was found to be both ATM and p53 independent [ 125 ].…”

Section: Plk1 and Maintenance Of Dna Integritymentioning

confidence: 99%

The CINs of Polo-Like Kinase 1 in Cancer

Cunningham

MacAuley

Vizeacoumar

et al. 2020

Cancers

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Polo-like kinase 1 (PLK1) is overexpressed near ubiquitously across all cancer types and dysregulation of this enzyme is closely tied to increased chromosomal instability and tumor heterogeneity. PLK1 is a mitotic kinase with a critical role in maintaining chromosomal integrity through its function in processes ranging from the mitotic checkpoint, centrosome biogenesis, bipolar spindle formation, chromosome segregation, DNA replication licensing, DNA damage repair, and cytokinesis. The relation between dysregulated PLK1 and chromosomal instability (CIN) makes it an attractive target for cancer therapy. However, clinical trials with PLK1 inhibitors as cancer drugs have generally displayed poor responses or adverse side-effects. This is in part because targeting CIN regulators, including PLK1, can elevate CIN to lethal levels in normal cells, affecting normal physiology. Nevertheless, aiming at related genetic interactions, such as synthetic dosage lethal (SDL) interactions of PLK1 instead of PLK1 itself, can help to avoid the detrimental side effects associated with increased levels of CIN. Since PLK1 overexpression contributes to tumor heterogeneity, targeting SDL interactions may also provide an effective strategy to suppressing this malignant phenotype in a personalized fashion.

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The CDK-PLK1 axis targets the DNA damage checkpoint sensor protein RAD9 to promote cell proliferation and tolerance to genotoxic stress

Cited by 20 publications

References 78 publications

Integrating DNA damage repair with the cell cycle

Integrating DNA damage repair with the cell cycle

Regulating a key mitotic regulator, polo‐like kinase 1 (PLK1)

The CINs of Polo-Like Kinase 1 in Cancer

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