It takes three to the DNA damage response tango

Schlam-Babayov, Sapir; Ziv, Yael; Shiloh, Yosef

doi:10.1080/23723556.2021.1881395

Cited by 6 publications

(1 citation statement)

References 10 publications

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“…Phosphorylation is catalyzed by protein kinases and reversed by protein phosphatases, and serves as a molecular switch, modulating the activity, structure, half-life, localization, and interacting partners of target proteins. Checkpoint activation and DNA repair are mainly regulated by the extensively studied master kinases, the Ataxia–telangiectasia and Rad3-related (ATR), Ataxia–telangiectasia mutated (ATM), and DNA-dependent protein kinases (DNA-PK) [ 10 ], as well as their effectors, Checkpoint kinase 1 (Chk1) and Checkpoint kinase 2/Radiation-sensitive 53 (Chk2/RAD53, mammal/yeast nomenclature) [ 11 ]. However, dynamic phosphorylation and dephosphorylation of DDR regulators and executor molecules are critical for successful DNA repair and maintenance of genome integrity.…”

Section: Introductionmentioning

confidence: 99%

Protein Phosphatase 4 Is Required for Centrobin Function in DNA Damage Repair

Réthi-Nagy,

Ábrahám,

Sinka

et al. 2023

Cells

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Genome stability in human cells relies on the efficient repair of double-stranded DNA breaks, which is mainly achieved by homologous recombination (HR). Among the regulators of various cellular functions, Protein phosphatase 4 (PP4) plays a pivotal role in coordinating cellular response to DNA damage. Meanwhile, Centrobin (CNTRB), initially recognized for its association with centrosomal function and microtubule dynamics, has sparked interest due to its potential contribution to DNA repair processes. In this study, we investigate the involvement of PP4 and its interaction with CNTRB in HR-mediated DNA repair in human cells. Employing a range of experimental strategies, we investigate the physical interaction between PP4 and CNTRB and shed light on the importance of two specific motifs in CNTRB, the PP4-binding FRVP and the ATR kinase recognition SQ sequences, in the DNA repair process. Moreover, we examine cells depleted of PP4 or CNTRB and cells harboring FRVP and SQ mutations in CNTRB, which result in similar abnormal chromosome morphologies. This phenomenon likely results from the impaired resolution of Holliday junctions, which serve as crucial intermediates in HR. Taken together, our results provide new insights into the intricate mechanisms of PP4 and CNTRB-regulated HR repair and their interrelation.

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Section: Introductionmentioning

confidence: 99%

Protein Phosphatase 4 Is Required for Centrobin Function in DNA Damage Repair

Réthi-Nagy,

Ábrahám,

Sinka

et al. 2023

Cells

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Chemo-phosphoproteomic profiling with ATR inhibitors berzosertib and gartisertib uncovers new biomarkers and DNA damage response regulators

Jadav

Weiland

Noordermeer

et al. 2023

Preprint

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The ATR kinase protects cells against DNA damage and replication stress and represents a promising anti-cancer drug target. The ATR inhibitors (ATRi) berzosertib and gartisertib are in clinical trials for treatment of advanced solid tumours as monotherapy or in combination with genotoxic agents. However, the pharmacodynamic ATR biomarker phospho-CHK1 has shown limited sensitivity in for quantitative assessment of ATR activity in clinical trials. Therefore, better biomarkers are needed, and with this in mind we carried out quantitative phospho-proteomic screening for ATR biomarkers that are highly sensitive to berzosertib and gartisertib. Screening identified novel ATR-dependent targets in three broad classes: i) targets whose phosphorylation is highly sensitive to ATRi; ii) novel targets with known genome maintenance roles; iii) novel targets whose cellular roles are unclear, including SCAF1. We show that SCAF1 interacts with RNAPII in a phospho-dependent manner and suppresses homologous recombination in cells lacking the BRCA1 tumour suppressor. Taken together these data reveal potential new ATR biomarkers and new genome maintenance factors.

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Protein phosphatase 4 is required for Centrobin function in DNA damage repair

Réthi‐Nagy

Ábrahám

Sinka

et al. 2023

Preprint

View full text Add to dashboard Cite

Genome stability in human cells relies on the efficient repair of double-stranded DNA breaks, which is mainly achieved by homologous recombination (HR). Among the regulators of various cellular functions, Protein Phosphatase 4 (PP4) plays a pivotal role in coordinating cellular response to DNA damage. Meanwhile, Centrobin (Ctb), initially recognized for its association with centrosomal function and microtubule dynamics, has sparked interest due to its potential contribution to DNA repair processes. In this study, we investigate the involvement of PP4 and its interaction with Ctb in HR-mediated DNA repair in human cells. Employing a range of experimental strategies, we investigate the physical interaction between PP4 and Ctb and shed light on the importance of two specific motifs in Ctb, the PP4-binding FRVP and the ATR kinase recognition SQ sequences, in DNA repair process. Moreover, we examine cells depleted of PP4 or Ctb and cells harboring FRVP and SQ mutations in Ctb, which result in similar abnormal chromosome morphologies. This phenomenon likely results from the impaired resolution of Holliday junctions, which serve as crucial intermediates in HR. Taken together, our results provide new insights into the intricate mechanisms of PP4 and Ctb-regulated HR repair and their interrelation.

show abstract

It takes three to the DNA damage response tango

Cited by 6 publications

References 10 publications

Protein Phosphatase 4 Is Required for Centrobin Function in DNA Damage Repair

Protein Phosphatase 4 Is Required for Centrobin Function in DNA Damage Repair

Chemo-phosphoproteomic profiling with ATR inhibitors berzosertib and gartisertib uncovers new biomarkers and DNA damage response regulators

Protein phosphatase 4 is required for Centrobin function in DNA damage repair

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