The Conserved Lys-95 Charged Residue Cluster Is Critical for the Homodimerization and Enzyme Activity of Human Ribonucleotide Reductase Small Subunit M2

Chen, Xinhuan; Xu, Zhijian; Zhang, Lingna; Liu, Hongchuan; Liu, Xia; Meng, Liang; Zhu, Lijun; Huang, Bingding; Yang, Cai‐Guang; Zhu, Weiliang; Shao, Jimin

doi:10.1074/jbc.m113.524546

Cited by 5 publications

(1 citation statement)

References 57 publications

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“…Restoration of YAP activity alleviated replicative senescence of MSCs via delaying RT‐associated G1 arrest and genome instability. Mechanistically, we identified RRM2, a crucial G1/S licensor (Chen et al, 2014 ), as the direct downstream of YAP in regulating RT‐associated cell cycle arrest. Besides, Hippo‐off YAP 2SA delayed the onset of genome instability and meanwhile enhanced DNA damage response/repair, which alleviated genome instability in the proceeding of RT development.…”

Section: Discussionmentioning

confidence: 96%

Releasing YAP dysfunction‐caused replicative toxicity rejuvenates mesenchymal stem cells

Yao

et al. 2023

Aging Cell

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Hippo‐independent YAP dysfunction has been demonstrated to cause chronological aging of stromal cells by impairing the integrity of nuclear envelope (NE). In parallel with this report, we uncover that YAP activity also controls another type of cellular senescence, the replicative senescence in in vitro expansion of mesenchymal stromal cells (MSCs), but this event is Hippo phosphorylation‐dependent, and there exist another NE integrity‐independent downstream mechanisms of YAP. Specifically, Hippo phosphorylation causes reduced nuclear/active YAP and then decreases the level of YAP protein in the proceeding of replicative senescence. YAP/TEAD governs RRM2 expression to release replicative toxicity (RT) via licensing G1/S transition. Besides, YAP controls the core transcriptomics of RT to delay the onset of genome instability and enhances DNA damage response/repair. Hippo‐off mutations of YAP (YAPS127A/S381A) satisfactorily release RT via maintaining cell cycle and reducing genome instability, finally rejuvenating MSCs and restoring their regenerative capabilities without risks of tumorigenesis.

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Section: Discussionmentioning

confidence: 96%

Releasing YAP dysfunction‐caused replicative toxicity rejuvenates mesenchymal stem cells

Yao

et al. 2023

Aging Cell

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Non-enzymatic action of RRM1 protein upregulates PTEN leading to inhibition of colorectal cancer metastasis

Meng

Chen

et al. 2015

Tumor Biol.

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Ribonucleotide reductase large subunit M1 (RRM1) forms a holoenzyme with small subunits to provide deoxyribonucleotides for DNA synthesis and cell proliferation. Here, we reported a non-RR role of the catalytic subunit protein RRM1 and related pathway in inhibiting colorectal cancer (CRC) metastasis. Ectopic overexpression of the wild-type RRM1, and importantly, its Y738F mutant that lacks RR enzymatic activity, prevented the migration and invasion of CRC cells by promoting phosphatase and tensin homolog on chromosome 10 (PTEN) transactivation. Furthermore, overexpression of the wild-type and RR-inactive mutant RRM1 similarly reduced the phosphorylation of Akt and increased the E-cadherin expression in CRC cells, which were blocked by PTEN knockdown attenuation. Examination of clinical CRC specimens demonstrated that both RRM1 protein expression and RR activity were elevated in most cancer tissues compared to the paired normal tissues. However, while RR activity did not change significantly in different cancer stages, the RRM1 protein level was significantly increased at stages T1-3 but decreased at stage T4, in parallel with the PTEN expression level and negatively correlated with invasion and liver metastasis. Thus, we propose that RRM1 protein can inhibit CRC invasion and metastasis at the advanced stage by regulating PTEN transactivation and its downstream pathways in addition to forming an RR holoenzyme for supporting cancer proliferation. Understanding of the seemingly contrary dual roles of RRM1 protein may further help to explain the complex mechanisms by which this key enzyme and its components are involved in cancer development.

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ATR–CHK1–E2F3 signaling transactivates human ribonucleotide reductase small subunit M2 for DNA repair induced by the chemical carcinogen MNNG

Gong

Liu

Song

et al. 2016

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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The Conserved Lys-95 Charged Residue Cluster Is Critical for the Homodimerization and Enzyme Activity of Human Ribonucleotide Reductase Small Subunit M2

Cited by 5 publications

References 57 publications

Releasing YAP dysfunction‐caused replicative toxicity rejuvenates mesenchymal stem cells

Releasing YAP dysfunction‐caused replicative toxicity rejuvenates mesenchymal stem cells

Non-enzymatic action of RRM1 protein upregulates PTEN leading to inhibition of colorectal cancer metastasis

ATR–CHK1–E2F3 signaling transactivates human ribonucleotide reductase small subunit M2 for DNA repair induced by the chemical carcinogen MNNG

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