The Role of DNA Damage and Repair in Neurotoxicity Caused by Cancer Therapies

Author(s):  
Djane Braz Duarte ◽  
Michael R. Vasko
2021 ◽  
Vol 22 (10) ◽  
pp. 5112
Author(s):  
Lotte van Beek ◽  
Éilís McClay ◽  
Saleha Patel ◽  
Marianne Schimpl ◽  
Laura Spagnolo ◽  
...  

Poly (ADP-ribose) polymerases (PARP) 1-3 are well-known multi-domain enzymes, catalysing the covalent modification of proteins, DNA, and themselves. They attach mono- or poly-ADP-ribose to targets using NAD+ as a substrate. Poly-ADP-ribosylation (PARylation) is central to the important functions of PARP enzymes in the DNA damage response and nucleosome remodelling. Activation of PARP happens through DNA binding via zinc fingers and/or the WGR domain. Modulation of their activity using PARP inhibitors occupying the NAD+ binding site has proven successful in cancer therapies. For decades, studies set out to elucidate their full-length molecular structure and activation mechanism. In the last five years, significant advances have progressed the structural and functional understanding of PARP1-3, such as understanding allosteric activation via inter-domain contacts, how PARP senses damaged DNA in the crowded nucleus, and the complementary role of histone PARylation factor 1 in modulating the active site of PARP. Here, we review these advances together with the versatility of PARP domains involved in DNA binding, the targets and shape of PARylation and the role of PARPs in nucleosome remodelling.


2014 ◽  
Vol 4 (Suppl 1) ◽  
pp. O21
Author(s):  
Tze Khee Chan ◽  
Xin Yi Loh ◽  
Daniel WS Tan ◽  
Bevin P Engelward ◽  
Fred WS Wong

2019 ◽  
Vol 48 (1) ◽  
pp. 68
Author(s):  
Michael E. Devitt ◽  
Robert Dreicer

<p>The aim of this article is to review the current role of genomic testing in the risk, prognosis, and treatment of genitourinary malignancies. The authors selected guidelines, publications, and abstracts relevant to the current and emerging role of genomics in genitourinary cancers. The risk of developing genitourinary cancer can be stratified based on genomic data. Prostate cancer has the strongest degree of heritability, with <em>BRCA1/2 </em>and <em>HOXB13 </em>mutations playing a role in familial disease. Genomic data is on the verge of informing treatment decisions across genitourinary cancers. mCRPC has diverse genomic alterations that represent potential therapeutic targets, including alterations in the AR pathway, DNA damage and repair pathways, cell cycle pathways, PI3K pathway, and Wnt signaling. Genomic alterations in clear cell renal cell carcinoma can inform prognosis and mutations in mTOR pathways predict response to mTOR inhibitors. Urothelial carcinoma can be classified into different subtypes based on gene expression profiling, which provides prognostic information and predicts response to chemotherapy and immunotherapy. Specific mutations have been identified that predict response to therapy including <em>ERCC2 </em>mutations and cisplatin, DNA damage and repair mutations and checkpoint inhibitors, and <em>FGFR3 </em>mutations and FGFR tyrosine kinase inhibitors such as erdafitinib.</p><p><strong>Conclusion. </strong>Genitourinary malignancies have not felt the impact of genomic data as greatly as other cancer types. The majority of benefit lies in identifying patients at high risk of genitourinary cancer. Fortunately, breakthroughs are on the horizon that will result in a greater incorporation of genomic information into treatment decisions for patients with genitourinary cancer.</p>


2008 ◽  
Vol 134 (4) ◽  
pp. A-785
Author(s):  
Xiuying Zhang ◽  
Shingo Tachibana ◽  
Bin Gao ◽  
George M. Williams ◽  
Zhaoli Sun

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