Src family kinases maintain the balance between replication stress and the replication checkpoint

Miura, Takahito; Fukumoto, Yasunori; Morii, Mariko; Honda, Takeshi; Yamaguchi, Noritaka; Nakayama, Yuji; Yamaguchi, Naoto

doi:10.1002/cbin.10517

Cited by 6 publications

(4 citation statements)

References 55 publications

(133 reference statements)

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“…This is reminiscent of the (opposite) activity regulation of Src-family kinases, which are kept inactive by a tyrosine phosphorylated C-terminal tail that prevents substrate recruitment by the N-terminal SH2 domain [27][28][29]. Src-family kinases suppress the replication checkpoint [28,29]. We speculate that this function of Srclike kinases is (partially) mediated by PP1:NIPP1 activation and the associated dephosphorylation of FHA ligands (Fig.…”

Section: Discussionmentioning

confidence: 93%

“…Src‐family kinases suppress the replication checkpoint [28,29]. We speculate that this function of Src‐like kinases is (partially) mediated by PP1:NIPP1 activation and the associated dephosphorylation of FHA ligands (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…8A). This is reminiscent of the (opposite) activity regulation of Src-family kinases, which are kept inactive by a tyrosine phosphorylated C-terminal tail that prevents substrate recruitment by the N-terminal SH2 domain [27][28][29]. Src-family kinases suppress the replication checkpoint [28,29].…”

Section: Discussionmentioning

confidence: 99%

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DNA damage‐induced allosteric activation of protein phosphatase PP1:NIPP1 through Src kinase‐induced circularization of NIPP1

Wu,

Van der Hoeven,

Claes

et al. 2024

The FEBS Journal

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Protein phosphatase‐1 (PP1) complexed to nuclear inhibitor of PP1 (NIPP1) limits DNA repair through dephosphorylation of NIPP1‐recruited substrates. However, the PP1:NIPP1 holoenzyme is completely inactive under basal conditions, hinting at a DNA damage‐regulated activation mechanism. Here, we report that DNA damage caused the activation of PP1:NIPP1 after a time delay of several hours through phosphorylation of NIPP1 at the C‐terminal tyrosine 335 (Y335) by a Src‐family kinase. PP1:NIPP1 activation partially resulted from the dissociation of the C terminus of NIPP1 from the active site of PP1. In addition, the released Y335‐phosphorylated C terminus interacted with the N terminus of NIPP1 to enhance substrate recruitment by the flanking forkhead‐associated (FHA) domain. Constitutive activation of PP1:NIPP1 by knock‐in of a phospho‐mimicking (Y335E) NIPP1 mutant led to the hypo‐phosphorylation of FHA ligands and an accumulation of DNA double‐strand breaks. Our data indicate that PP1:NIPP1 activation through circularization of NIPP1 is a late response to DNA damage that contributes to the timely recovery from damage repair.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

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DNA damage‐induced allosteric activation of protein phosphatase PP1:NIPP1 through Src kinase‐induced circularization of NIPP1

Wu,

Van der Hoeven,

Claes

et al. 2024

The FEBS Journal

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“…Src knockout reduced primary tumor growth and metastasis (24). Although SRC activation is known to be required for checkpoint recovery termination and SRC inhibition delays G2 DNA damage checkpoint recovery following DNA doublestrand break (DSB) repair (25,26), the role of SRC in DDR is incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

Attenuation of SRC Kinase Activity Augments PARP Inhibitor–mediated Synthetic Lethality in BRCA2-altered Prostate Tumors

Chakraborty

Patail

Hirani

et al. 2020

Clinical Cancer Research

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Purpose: Alterations in DNA damage repair (DDR) pathway genes occur in 20-25% of men with metastatic castration-resistant prostate cancer (mCRPC). Although poly (adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPi) have been shown to benefit men with mCRPC harboring DDR defects due to mutations in BRCA1/2 and ATM, additional treatments are necessary because the effects are not durable. Experimental Design:We performed transcriptomic analysis of publicly available mCRPC cases, comparing BRCA2-null to BRCA2 wild type. We generated BRCA2-null prostate cancer cells using CRISPR/Cas9 and treated these cells with PARPi and SRC inhibitors. We also assessed the antiproliferative effects of combination treatment in 3D prostate cancer organoids. Results:We observed significant enrichment of the SRC signaling pathway in BRCA2-altered mCRPC. BRCA2-null prostate cancer cell lines had increased SRC phosphorylation and higher

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Unravelling the molecular basis of PARP inhibitor resistance in prostate cancer with homologous recombination repair deficiency

Zaman,

Kushwah,

Badriprasad

et al. 2024

International Review of Cell and Molecular Biology

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Src family kinases maintain the balance between replication stress and the replication checkpoint

Cited by 6 publications

References 55 publications

DNA damage‐induced allosteric activation of protein phosphatase PP1:NIPP1 through Src kinase‐induced circularization of NIPP1

DNA damage‐induced allosteric activation of protein phosphatase PP1:NIPP1 through Src kinase‐induced circularization of NIPP1

Attenuation of SRC Kinase Activity Augments PARP Inhibitor–mediated Synthetic Lethality in BRCA2-altered Prostate Tumors

Unravelling the molecular basis of PARP inhibitor resistance in prostate cancer with homologous recombination repair deficiency

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