Structure insights into the molecular mechanism of the interaction between UHRF2 and PCNA

Chen, Wanbiao; Wu, Mingzai; Hang, Tianrong; Wang, Chengliang; Zhang, Xuan; Zang, Jianye

doi:10.1016/j.bbrc.2017.09.102

Cited by 11 publications

(15 citation statements)

References 19 publications

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“…UHRF2 generally is deemed to be a nuclear E3 ubiquitin ligase which is involved in cell cycle and epigenetic regulation. UHRF2 was reported to interact with many key factors in cell cycle 4 , 7 , 26 . Our result indicated that loss of UHRF2 can promote NSCLC cell entering S or G2 phase.…”

Section: Discussionmentioning

confidence: 99%

“…UHRF2 (ubiquitin like with PHD and ring finger domains 2) includes UBL, PHD, TTD, SET and RING-associated (SRA/YDG) and RING finger domains 3 . Due to its multiple domains, UHRF2 has a complex function, including as a cell cycle regulator, regulating genomic stability and epigenetics 4 . Recently, some studies reported UHRF2 was involved in various human diseases, especially in cancer, however, its exact roles in cancer are still in dispute.…”

Section: Introductionmentioning

confidence: 99%

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Loss of UHRF2 Is Associated With Non-small Cell Lung Carcinoma Progression

Chun¹,

Xiong²,

Li³

et al. 2018

J. Cancer

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Recent evidence indicated ubiquitin like with PHD and ring finger domains 2 (UHRF2) was involved in various human diseases, especially in cancer, however, its roles in cancer are still in dispute. Here, we found UHRF2 expression was decreased in lung cancer tissues compared with adjacent normal tissues by referring to the Oncomine Database, which was further identified by immunoblotting and quantitative real-time polymerase chain reaction assays. Secondly, we found knockdown of UHRF2 in A549 and 95-D cell lines enhanced the capability of proliferation, invasion and migration, while forced UHRF2 expression inhibited NSCLC cells proliferation,invasion and migration. Mechanistically, dot-blot and western blot assays indicated that the level of UHRF2 was positively correlated with 5-hmC level by affecting ten-eleven translocation 2 (TET2) expression. Clinically, UHRF2 downregulation is significantly correlated with a malignant phenotype, including larger tumor size and poor differentiation. Moreover, UHRF2 downregulated correlates with shorter overall survival(OS).Conclusion: Our findings indicate that UHRF2 is a tumor suppressor in NSCLC by influence TET2 expression and serve as a potential therapeutic target in NSCLC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Loss of UHRF2 Is Associated With Non-small Cell Lung Carcinoma Progression

Chun¹,

Xiong²,

Li³

et al. 2018

J. Cancer

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“…Pol κ contains a position 5 Asp866, and pol η includes the acidic Glu705 P5 , both of these residues interact with the PCNA His44 side chain . A number of other PCNA–peptide structures display a key interaction with PCNA His44, including a UHRF2 peptide for which no binding was observed when assayed against a His44Ala PCNA mutant . Formation of the 3 10 ‐helix is necessary to orientate the acidic side chain of a residue at position 5 towards PCNA His44.…”

Section: Pip‐box Divergencementioning

confidence: 99%

“…[19] An umber of other PCNA-peptide structures display ak ey interaction with PCNA His44, including aU HRF2p eptide for which no binding was observed when assayed against aH is44AlaP CNA mutant. [25] Formation of the 3 10 -helix is necessary to orientate the acidic side chain of ar esidueatposition5towards PCNA His44. Interestinglyi np 21, the Thr148 at position5 does not make any notable hydrogen bonds to PCNA.…”

Section: Pip-box Divergencementioning

confidence: 99%

Targeting PCNA with Peptide Mimetics for Therapeutic Purposes

2019

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Proliferating cell nuclear antigen (PCNA) is an excellent inhibition target to shut down highly proliferative cells and thereby develop a broad‐spectrum cancer therapeutic. It interacts with a wide variety of proteins through a conserved motif referred to as the PCNA‐interacting protein (PIP) box. There is large sequence diversity between high‐affinity PCNA binding partners, but with conservation of the binding structure—a well‐defined 310‐helix. Herein, all current PIP‐box peptides crystallised with human PCNA are collated to reveal common trends between binding structure and affinity. Key intra‐ and intermolecular hydrogen‐bonding networks that stabilise the 310‐helix of PIP‐box partners are highlighted and related back to the canonical PIP‐box motif. High correlation with the canonical PIP‐box sequence does not directly afford high affinity. Instead, we summarise key interactions that stabilise the binding structure that leads to enhanced PCNA binding affinity. These interactions also implicate the “non‐conserved” residues within the PIP‐box that have previously been overlooked. Such insights will allow a more directed approach to develop therapeutic PCNA inhibitors.

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“…UHRF2 is not very well characterized, however it has been shown to be important in cell cycle progression and can cause G1 phase cell cycle arrest through its interaction with the Cdk2–cyclin E complex [ 14 , 15 ]. UHRF2 has been implicated in genome maintenance as it has been shown to interact with PCNA through a PIP box motif [ 16 ], additionally, UHRF2 was shown to be recruited to DNA damage sites, primarily through its TTD-PHD and SRA domains [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Identification of UHRF2 as a novel DNA interstrand crosslink sensor protein

et al. 2018

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The Fanconi Anemia (FA) pathway is important for repairing interstrand crosslinks (ICLs) between the Watson-Crick strands of the DNA double helix. An initial and essential stage in the repair process is the detection of the ICL. Here, we report the identification of UHRF2, a paralogue of UHRF1, as an ICL sensor protein. UHRF2 is recruited to ICLs in the genome within seconds of their appearance. We show that UHRF2 cooperates with UHRF1, to ensure recruitment of FANCD2 to ICLs. A direct protein-protein interaction is formed between UHRF1 and UHRF2, and between either UHRF1 and UHRF2, and FANCD2. Importantly, we demonstrate that the essential monoubiquitination of FANCD2 is stimulated by UHRF1/UHRF2. The stimulation is mediating by a retention of FANCD2 on chromatin, allowing for its monoubiquitination by the FA core complex. Taken together, we uncover a mechanism of ICL sensing by UHRF2, leading to FANCD2 recruitment and retention at ICLs, in turn facilitating activation of FANCD2 by monoubiquitination.

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Structure insights into the molecular mechanism of the interaction between UHRF2 and PCNA

Cited by 11 publications

References 19 publications

Loss of UHRF2 Is Associated With Non-small Cell Lung Carcinoma Progression

Loss of UHRF2 Is Associated With Non-small Cell Lung Carcinoma Progression

Targeting PCNA with Peptide Mimetics for Therapeutic Purposes

Identification of UHRF2 as a novel DNA interstrand crosslink sensor protein

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