Phosphorylation Alters the Properties of Pol η: Implications for Translesion Synthesis

Peddu, Chandana; Zhang, Sufang; Zhao, Hong; Wong, Agnes; Lee, Ernest Y.C.; Lee, Marietta Y.W.T.; Zhang, Zhongtao

doi:10.1016/j.isci.2018.07.009

Cited by 13 publications

(14 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In line with our finding that Cdc28 -dependent phosphorylation was important for Polη function in response to damage, phosphorylation of human Polη after UV irradiation is required for localization to sites of lesions, and contributes to cell survival after UV exposure ( Chen et al 2008 ; Bertoletti et al 2017 ; Peddu et al 2018 ). As opposed to the human counterpart, however, nuclear accumulation of yeast Polη seems to be independent of the DNA damage response, since WT Polη and the Polη-S14A mutant both accumulated in the nucleus in the absence of break induction, and were insensitive to UV irradiation ( Figures 2B and 5B and Figure S3).…”

Section: Discussionsupporting

confidence: 89%

“…Polη ubiquitination, for example, restricts its accessibility to replication forks ( Cipolla et al 2019 ). In addition, phosphorylation of human Polη is required for its localization to sites of UV-induced DNA lesions ( Chen et al 2008 ; Bertoletti et al 2017 ; Peddu et al 2018 ). These findings prompted us to investigate whether Polη would be regulated through post-translational modification(s) also for formation of damage-induced cohesion.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Post-translational Regulation of DNA Polymerase η, a Connection to Damage-Induced Cohesion in Saccharomyces cerevisiae

Enervald

Joelsson

et al. 2020

Genetics

View full text Add to dashboard Cite

Double-strand breaks that are induced postreplication trigger establishment of damage-induced cohesion in Saccharomyces cerevisiae, locally at the break site and genome-wide on undamaged chromosomes. The translesion synthesis polymerase, polymerase η, is required for generation of damage-induced cohesion genome-wide. However, its precise role and regulation in this process is unclear. Here, we investigated the possibility that the cyclin-dependent kinase Cdc28 and the acetyltransferase Eco1 modulate polymerase η activity. Through in vitro phosphorylation and structure modeling, we showed that polymerase η is an attractive substrate for Cdc28. Mutation of the putative Cdc28-phosphorylation site Ser14 to Ala not only affected polymerase η protein level, but also prevented generation of damage-induced cohesion in vivo. We also demonstrated that Eco1 acetylated polymerase η in vitro. Certain nonacetylatable polymerase η mutants showed reduced protein level, deficient nuclear accumulation, and increased ultraviolet irradiation sensitivity. In addition, we found that both Eco1 and subunits of the cohesin network are required for cell survival after ultraviolet irradiation. Our findings support functionally important Cdc28-mediated phosphorylation, as well as post-translational modifications of multiple lysine residues that modulate polymerase η activity, and provide new insights into understanding the regulation of polymerase η for damage-induced cohesion.

show abstract

Section: Discussionsupporting

confidence: 89%

mentioning

confidence: 99%

Post-translational Regulation of DNA Polymerase η, a Connection to Damage-Induced Cohesion in Saccharomyces cerevisiae

Enervald

Joelsson

et al. 2020

Genetics

View full text Add to dashboard Cite

show abstract

“…This process is required for cell survival following UV exposure and thereby provides an association between UV‐induced cell cycle arrest and TLS. Another study was performed by Peddu et al (2018) and they shown that phosphorylation of Pol η increases its affinity for ub‐PCNA, and thus impacts TLS regulation. They also demonstrated that, PDIP38 sequestered the Pol η away from the replication machinery, and prevents it from interfering with high fidelity polymerases in normal cells.…”

Section: Pol η Escalating Tlsmentioning

confidence: 99%

DNA polymerase eta: A potential pharmacological target for cancer therapy

Saha

Mandal

Talukdar

et al. 2020

Journal Cellular Physiology

View full text Add to dashboard Cite

In the last two decades, intensive research has been carried out to improve the survival rates of cancer patients. However, the development of chemoresistance that ultimately leads to tumor relapse poses a critical challenge for the successful treatment of cancer patients. Many cancer patients experience tumor relapse and ultimately die because of treatment failure associated with acquired drug resistance. Cancer cells utilize multiple lines of self-defense mechanisms to bypass chemotherapy and radiotherapy. One such mechanism employed by cancer cells is translesion DNA synthesis (TLS), in which specialized TLS polymerases bypass the DNA lesion with the help of monoubiquitinated proliferating cell nuclear antigen. Among all TLS polymerases (Pol η, Pol ι, Pol κ, REV1, Pol ζ, Pol μ, Pol λ, Pol ν, and Pol θ), DNA polymerase eta (Pol η) is well studied and majorly responsible for the bypass of cisplatin and UV-induced DNA damage. TLS polymerases contribute to chemotherapeutic drug-induced mutations as well as therapy resistance. Therefore, targeting these polymerases presents a novel therapeutic strategy to combat chemoresistance. Mounting evidence suggests that inhibition of Pol η may have multiple impacts on cancer therapy such as sensitizing cancer cells to chemotherapeutics, suppressing drug-induced mutagenesis, and inhibiting the development of secondary tumors. Herein, we provide a general introduction of Pol η and its clinical implications in blocking acquired drug resistance. In addition; this review addresses the existing gaps and challenges of Pol η mediated TLS mechanisms in human cells. A better understanding of the Pol η mediated TLS mechanism will not merely establish it as a potential pharmacological target but also open possibilities to identify novel drug targets for future therapy.

show abstract

“…Although PrimPol is required for replication fork progression under both normal and DNA-damaging conditions (40), the mutual exclusivity of PCNA/PrimPol binding to PCNA could help prevent aberrant PrimPol recruitment to the replication fork when PCNA is in complex with Pold. POLDIP2 has been reported to be phosphorylated on Ser 147 and Ser 150 by the ATR kinase following UV irradiation (36). These two serine residues are found immediately beside PIP2 ( Figure 1) and with phosphorylation adding bulky negatively charged groups, the binding properties of PIP2 would likely be changed.…”

Section: Structural Insights Into Poldip2 Interactions With Primpolmentioning

confidence: 99%

Crystal structure and molecular dynamics of human POLDIP2, a multifaceted adaptor protein in metabolism and genome stability

Kulik

Maruszczak

Thomas

et al. 2020

Preprint

View full text Add to dashboard Cite

Polymerase δ-interacting protein 2 (POLDIP2, PDIP38) is a multifaceted, ‘moonlighting’ protein, involved in binding protein partners from many different cellular processes, including mitochondrial metabolism, DNA replication and repair, and reactive oxygen species generation. POLDIP2 is found in multiple cellular compartments, potentially shuttled depending on its role. How POLDIP2 binds to and coordinates many different proteins is currently unknown. Towards this goal, we present the crystal structure of the ‘mitochondrial’ fragment of POLDIP2 to 2.8 Å. POLDIP2 exhibited a compact two-domain β-strand-rich globular structure, confirmed by circular dichroism and small angle X-ray scattering approaches. POLDIP2 comprised canonical DUF525 (ApaG) and YccV-like domains, but with the conserved domain linker packed tightly, resulting in an ‘extended’ YccV module. A central channel through POLDIP2 was observed which we hypothesise could influence structural changes potentially mediated by redox conditions, following observation of a modified cysteine residue in the channel. Unstructured regions were rebuilt by ab initio modelling to generate a model of full length POLDIP2. Molecular dynamics simulations revealed a highly dynamic N-terminal region tethered to the YccV-domain by an extended linker, potentially facilitating interactions with distal binding partners. Finally we build models of POLDIP2 interacting in complex with two of its partners in genome stability, PrimPol and PCNA. These indicate that dynamic flexibility of the POLDIP2 N-terminal and loop regions are critical to mediate protein-protein interactions.

show abstract

Phosphorylation Alters the Properties of Pol η: Implications for Translesion Synthesis

Cited by 13 publications

References 67 publications

Post-translational Regulation of DNA Polymerase η, a Connection to Damage-Induced Cohesion in Saccharomyces cerevisiae

Post-translational Regulation of DNA Polymerase η, a Connection to Damage-Induced Cohesion in Saccharomyces cerevisiae

DNA polymerase eta: A potential pharmacological target for cancer therapy

Crystal structure and molecular dynamics of human POLDIP2, a multifaceted adaptor protein in metabolism and genome stability

Contact Info

Product

Resources

About