Ribosomal protein L6 (RPL6) is recruited to DNA damage sites in a poly(ADP-ribose) polymerase–dependent manner and regulates the DNA damage response

Yang, Chuanzhen; Zang, Weicheng; Ji, Yapeng; Li, Tingting; Yang, Yongfeng; Zheng, Xiaofeng

doi:10.1074/jbc.ra118.007009

Cited by 44 publications

(36 citation statements)

References 48 publications

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“…Similarly, some RPs have been implicated in processes independent of translation, most notably regulation of p53 degradation (27). Here, we demonstrate that SBDS and RPS19 also have roles in DNA DSB repair.…”

Section: Discussionsupporting

confidence: 55%

“…Specifically, eIF6 depletion did not rescue the HR defect, as would be expected if ribosome subunit joining was restored ( Figure 3A); EFL1 depletion did not phenocopy the HR defect of SBDS-deficient cells ( Figure 3B), as would be expected if impaired ribosome subunit joining was central to the phenotype; and both SBDS and RPS19 were recruited to sites of an induced DSB ( Figure 9). While the association of these proteins with DSBs is novel, a few other ribosomal proteins, RPL6, RPL8 and RPS14, but not RPL9, have been shown previously to be recruited to sites of DNA damage-induced by laser microirradiation (27). RPL6 recruitment occurs via interaction with H2A and in a PARP-dependent fashion.…”

Section: Discussionmentioning

confidence: 99%

“…A recent study reported that RPL6 was rapidly recruited to sites of DNA damage induced by laser microirradiation (27). Thus, we tested whether the SBDS and RPS19 proteins might also function more directly in DSB repair through localization to DSBs.…”

Section: Sbds and Rps19 Are Found In The Vicinity Of Dsbmentioning

confidence: 98%

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Homologous recombination defects in Shwachman-Diamond syndrome and Diamond-Blackfan anemia

Asik¹,

Chatterjee²,

Bertuch³

2020

Preprint

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Shwachman-Diamond syndrome (SDS) and Diamond-Blackfan anemia (DBA) are ribosomopathies characterized by impaired hematopoiesis and cancer predisposition. The mechanisms underlying cancer predisposition in these disorders are not well understood. We found that LCLs derived from patients with SDS or DBA had a prolonged DNA damage response and hypersensitivity to ionizing radiation, suggesting impaired DNA double strand break (DSB) repair. Consistent with this, depletion of SBDS and RPS19, the most common etiologic factors in SDS and DBA, respectively, resulted in reduced homologous recombination (HR) in HCT116 and U2OS cells. Surprisingly, depletion of EFL1, which functions with SBDS in ribosome biogenesis, did not impair HR and depletion of eIF6, which restores ribosome joining in SBDS-depleted cells, did not rescue the HR defect associated with SBDS depletion. Instead, we found SBDS and RPS19 recruitment to sites of DSBs suggesting that SBDS and RPS19 have more proximate roles in regulating HR, independent of their ribosomal functions. We propose that reduced HR shifts DSB repair toward error-prone NHEJ and this may contribute to oncogenesis in SDS and DBA. Additionally, we found SBDS and RPS19 depleted cells were hypersensitive to PARP inhibition, potentially uncovering a therapeutic target for SDS- and DBA-associated malignancies.

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

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Homologous recombination defects in Shwachman-Diamond syndrome and Diamond-Blackfan anemia

Asik¹,

Chatterjee²,

Bertuch³

2020

Preprint

View full text Add to dashboard Cite

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“…RPL6 was identified as an upregulated gene in multidrug‐resistant gastric cancer cells . Yang et al (2019) found that RPL6 could be recruited to DNA damage sites and regulated the DNA damage response, which suggests its nuclear localization. Then, focusing on RPL6, we confirmed that NSUN2 can directly interact with RPL6.…”

Section: Discussionmentioning

confidence: 99%

NOP2/Sun RNA methyltransferase 2 promotes tumor progression via its interacting partner RPL6 in gallbladder carcinoma

et al. 2019

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NOP2/Sun domain family, member 2 (NSUN2) is a nuclear RNA methyl‐transferase catalyzing 5‐methylcytosine formation. Evidence shows that NSUN2 is correlated with cell unlimited proliferation. However, its functional role in gallbladder carcinoma (GBC), which is the most common biliary tract malignancy and has a poor prognosis, remains to be determined. Here we found that NSUN2 was highly expressed in GBC tissues as well as cell lines. NSUN2 silencing repressed GBC cell proliferation and tumorigenesis both in vitro and in vivo. Conversely, upregulation of NSUN2 enhanced GBC cell growth and colony formation. We further discovered that RPL6 was a closely interacting partner with NSUN2. Silencing RPL6 resulted in insufficient NSUN2 translational level and accumulative NSUN2 transcriptional level. Exogenous expression of NSUN2 partially rescued the effect of RPL6 in gallbladder cancer progression. Taken together, our data provided novel mechanic insights into the function of NSUN2 in GBC, thus pointing to NSUN2 as a potential and effective therapeutic approach to GBC treatment.

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“…p53 plays an important role in DNA damage-induced G2/M checkpoint activation and in inhibiting entry into mitosis (Fernandez-Capetillo et al, 2002; Yang et al2018). In our previous report, we established the range of MTX doses that induces DNA breaks in mESCs.…”

Section: Discussionmentioning

confidence: 99%

Folate deficiency facilitates coordination of KDM6A with p53 in response to DNA damage

Gao

Zou

et al. 2019

Preprint

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Folate contributes to the accumulation of DNA strand breaks (DSBs) in the genome. Kdm6a plays a critical role in early embryogenesis but it is unknown whether Kdm6a is involved in the DNA damage response under folate deficiency. Here, we established a low folate environment for mouse embryonic cells using a folate antagonist (methotrexate, MTX). We found increased enrichment of DSBs in Kdm6a in MTX-treated cells, resulting in reduced Kdm6a expression. MTX treatment enriched KDM6A in the nonhomologous end-joining (NHEJ) repair pathway and controlled the expression of the Ku heterodimer (Ku70/80) and XRCC4. The activation of NHEJ repair pathway-associated genes under folate deficiency relied on the specific interaction between KDM6A and p53. p53 silencing increased Ku heterodimer expression. In addition, in a neural tube defect (NTD) mouse model and low folate neural tube defect human brain samples, KDM6A levels were also decreased and accompanied by over-expression of Ku80. Our findings highlight how alterations in folate levels affect KDM6A with respect to DNA breakage and DNA repair, offering a new insight into the molecular function of KDM6A.Summary statementOur study demonstrates for the first time that in mammals, Kdm6a and p53 have synergistic effects during DNA fragmentation repair.

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Ribosomal protein L6 (RPL6) is recruited to DNA damage sites in a poly(ADP-ribose) polymerase–dependent manner and regulates the DNA damage response

Cited by 44 publications

References 48 publications

Homologous recombination defects in Shwachman-Diamond syndrome and Diamond-Blackfan anemia

Homologous recombination defects in Shwachman-Diamond syndrome and Diamond-Blackfan anemia

NOP2/Sun RNA methyltransferase 2 promotes tumor progression via its interacting partner RPL6 in gallbladder carcinoma

Folate deficiency facilitates coordination of KDM6A with p53 in response to DNA damage

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